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US7795264B2 - Substituted arylpyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same - Google Patents

Substituted arylpyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same Download PDF

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US7795264B2
US7795264B2 US11/761,605 US76160507A US7795264B2 US 7795264 B2 US7795264 B2 US 7795264B2 US 76160507 A US76160507 A US 76160507A US 7795264 B2 US7795264 B2 US 7795264B2
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alkyl
heterocycloalkyl
cycloalkyl
hydrogen
optionally substituted
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Ingo Hartung
Georg Mendelstr Kettschau
Karl-Heinz Thierauch
Hans Briem
Philip Lienau
Antonius Ter Laak
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Bayer Intellectual Property GmbH
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • the present invention relates to substituted arylpyrazolopyridine compounds of general formula (I) and salts thereof, to pharmaceutical compositions comprising said substituted arylpyrazolopyridine compounds, to methods of preparing said substituted arylpyrazolopyridines as well as to the use thereof.
  • Dysregulated vascular growth plays a critical role in a variety of inflammatory diseases, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, rheumatoid arthritis and inflammatory bowl disease.
  • Aberrant vascular growth is also involved in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy.
  • sustained vascular growth is accepted as one hallmark of cancer development (Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57).
  • tumours initially grow either as an avascular mass or by co-opting existing host vessels, growth beyond a few mm 3 in size is depending on the induction of vessel neogrowth in order to sufficiently provide the tumour with oxygen and nutrients.
  • Induction of angiogenesis is a prerequisite that the tumour surpasses a certain size (the so called angiogenic switch).
  • An intricate signalling interaction network between cancer cells and the tumour microenvironment triggers the induction of vessel growth from existing vasculature.
  • the dependence of tumours on neovascularization has led to a new treatment paradigm in cancer therapy (Ferrara et al. Nature 2005, 438, 967; Carmeliet Nature 2005, 438, 932).
  • Blocking tumour neovascularization by small molecule or antibody-mediated inhibition of relevant signal transduction pathways holds a great promise for extending currently available therapy options.
  • angiogenesis involves the remodeling of the initial vasculature and sprouting of new vessels (Risau, W. Nature 1997, 386, 671; Jain, R. K. Nat. Med. 2003, 9, 685).
  • angiogenesis occurs in wound healing, muscle growth, the female cycle and in the above mentioned disease states.
  • receptor tyrosine kinases of the vascular endothelial growth factor (VEGF) family and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptor tyrosine kinases are essential for both developmental and disease-associated angiogenesis (Ferrara et al Nat. Med. 2003, 9, 669; Dumont et al. Genes Dev. 1994, 8, 1897; Sato et al. Nature 1995, 376, 70).
  • Tie2 receptor tyrosine kinase is selectively expressed on endothelial cells (EC) of the adult vasculature (Schlaeger et al. Proc. Nat. Acad. Sci. USA 1997, 94, 3058).
  • Immunohistochemical analysis demonstrated the expression of Tie2 in adult rat tissues undergoing angiogenesis.
  • Tie2 is expressed in neovessels of the developing corpus luteum.
  • Binding of Ang1 to Tie2 expressed on EC induces receptor cross-phosphorylation and kinase activation thus triggering various intracellular signalling pathways.
  • the intracellular C-terminal tail of the Tie2 protein plays a crucial role in Tie2 signalling (Shewchuk et al. Structure 2000, 8, 1105).
  • a conformational change is induced which removes the C-tail out of its inhibitory conformation thus allowing kinase activation by cross-phoshorylation of various Tyr residues in the C-tail, which subsequently function as docking sites for phosphotyrosine-binding (PTB) site possessing down-stream mediators.
  • PTB phosphotyrosine-binding
  • Ang1 activation of Tie2 includes inhibition of EC apoptosis, stimulation of EC migration and blood vessel reorganization, suppression of inflammatory gene expression and suppression of vascular permeability (Brindle et al. Circ. Res. 2006, 98, 1014). In contrast to VEGF-VEGFR signalling in EC, Ang1 activation of Tie2 does not stimulate EC proliferation in the majority of published assay settings.
  • the anti-apoptotic effect of Tie2 signalling was shown to be mediated mainly by the PI3K-Akt signalling axis which is activated by binding of the regulatory p85 subunit of PI3K to Y1102 in the Tie2 C-tail (DeBusk et al. Exp. Cell. Res. 2004, 298, 167; Papapetropoulos et al. J. Biol. Chem. 2000, 275, 9102; Kim et al. Circ. Res. 2000, 86, 24).
  • the chemotactic response downstream of the activated Tie2 receptor requires crosstalk between PI3K and the adaptor protein Dok-R.
  • PI3K-mediated recruitment of the adaptor protein ShcA to Y1102 of the Tie2 C-tail is also believed to induce cellular sprouting and motility effects involving activation of endothelial nitric oxide synthase (eNOS), focal adhesion kinase (FAK) and the GTPases RhoA and Rac1.
  • eNOS endothelial nitric oxide synthase
  • FK focal adhesion kinase
  • RhoA and Rac1 GTPases
  • Other downstream mediators of Tie2 signalling include the adaptor protein Grb2, which mediates Erk1/2 stimulation, and the SHP-2 phosphatase.
  • basal activation of the Tie2 pathway by Ang1 is believed to maintain quiescence and integrity of the endothelium of the adult vasculature by providing a cell survival signal for ECs and by maintaining the integrity of the EC lining of blood vessels (Peters et al. Recent Prog. Horm. Res. 2004, 59, 51).
  • Ang2 In contrast to Ang1, Ang2 is not able to activate Tie2 on EC unless Ang2 is present in high concentration or for prolonged periods. However, Ang2 functions as a Tie2 agonist in non-endothelial cells tranfected with Tie2. The structural basis for this context-dependence of the Ang2-Tie2 interaction is to date not understood.
  • Ang2 functions as Tie2 antagonist and thus blocks the agonistic activity of Ang1 (Maisonpierre et al. Science 1997, 277, 55). Ang2 binding to Tie2 prevents Ang1-mediated Tie2 activation which leads to vessel destabilization and results in vessel regression in the absence of pro-angiogenic stimuli such as VEGF. While Ang1 is widely expressed by periendothelial cells in quiescent vasculature such as pericytes or smooth muscle cells, Ang2 expression occurs in areas of ongoing angiogenesis. Ang2 can be stored in Weibel-Palade bodies in the cytoplasm of EC allowing for a quick vascular response upon stimulation.
  • Ang1 and Ang2 are expressed in the corpus luteum, with Ang2 localizing to the leading edge of proliferating vessels and Ang1 localizing diffusively behind the leading edge.
  • Ang2 expression is inter alia initiated by hypoxia (Pichiule et al. J. Biol. Chem. 2004, 279, 12171).
  • Ang2 is upregulated in the tumour vasculature and represents one of the earliest tumour markers.
  • Ang2 expression induces vessel permeability and—in the presence of e.g. pro-angiogenic VEGF—triggers angiogenesis. After VEGF mediated EC proliferation and vessel sprouting maturation of the newly formed vessels again necessitates Tie2 activation by Ang1.
  • Tie2 RTK an attractive target for anti-angiogenesis therapy in diseases caused by or associated with dysregulated vascular growth.
  • targeting the Tie2 pathway alone will be sufficient to achieve efficacious blockade of neovascularization.
  • Integrin ⁇ 5 ⁇ 1 associates constitutively with Tie2 and increases the receptor's binding affinity for Ang1 resulting in initiation of downstream signalling at lower Ang1 effector concentrations in situations where integrin ⁇ 5 ⁇ 1 is present.
  • the recently solved crystal structure of the Tie2-Ang2 complex suggests however that neither the oligomerization state nor a different binding mode causes the opposing cellular effects (Barton et al. Nat. Struc. Mol. Biol. 2006, advance online publication).
  • Ang1-Tie2 signalling plays also a role in the development of the lymphatic system and in lymphatic maintenance and sprouting (Tammela et al. Blood 2005, 105, 4642).
  • An intimate cross-talk between Tie2 and VEGFR-3 signalling in lymphangiogenesis seems to equal the Tie2-KDR cross-talk in blood vessel angiogenesis.
  • Tie2 signalling in the development and maintenance of the vasculature.
  • Disruption of Tie2 function in Tie2 ⁇ / ⁇ transgenic mice leads to early embryonic lethality between days 9.5 and 12.5 as a consequence of vascular abnormalities.
  • Tie2 ⁇ / ⁇ embryos fail to develop the normal vessel hierachy suggesting a failure of vascular branching and differentiation.
  • the heart and vessels in Tie2 ⁇ / ⁇ embryos show a decreased lining of EC and a loosened interaction between EC and underlying pericyte/smooth muscle cell matrix.
  • mice lacking functional Ang1 expression and mice overexpressing Ang2 display a phenotype reminiscent of the phenotype of Tie2 ⁇ / ⁇ mice (Suri et al. Cell 1996, 87, 1171).
  • Ang2 ⁇ / ⁇ mice have profound defects in the growth and patterning of lymphatic vasculature and fail to remodel and regress the hyaloid vasculature of the neonatal lens (Gale et al. Dev. Cell 2002, 3, 411).
  • Ang1 rescued the lymphatic defects, but not the vascular remodelling defects. Therefore, Ang2 might function as a Tie2 antagonist in blood vasculature but as a Tie2 agonist in developing lymph vasculature suggesting redundant roles of Ang1 and Ang2 in lymphatic development.
  • Tie2 pathway Aberrant activation of the Tie2 pathway is involved in various pathological settings. Activating Tie2 mutations leading to increased ligand-dependent and ligand-independent Tie2 kinase activity cause inherited venous malformations (Vikkula et al. Cell 1996, 87, 1181). Increased Ang1 mRNA and protein levels as well as increased Tie2 activation have been reported in patients with pulmonary hypertension (PH). Increased pulmonary arterial pressure in PH patients results from increased coverage of pulmonary arterioles with smooth muscle cells (Sullivan et al. Proc. Natl. Acad. Sci. USA 2003, 100, 12331).
  • Tie2 and the ligands Ang1 and Ang2 are greatly upregulated in lesions, whereas a significant decrease in expression of Tie2 and ligands occur under anti-psoriatic treatment (Kuroda et al. J. Invest. Dermatol 2001, 116, 713).
  • Direct association of pathogenesis of disease with Tie2 expression has been demonstrated recently in transgenic mice overexpressing Tie2 (Voskas et al. Am. J. Pathol. 2005, 166, 843).
  • a psoriasis-like phenotype such as epidermal thickening, rete ridges and lymphocyte infiltration.
  • Tie2 expression was investigated in human breast cancer specimens and Tie2 expression was found in the vascular endothelium both in normal breast tissue as well as in tumour tissue. The proportion of Tie2-positive microvessels was increased in tumours as compared to normal breast tissue (Peters et al. Br. J. Canc. 1998, 77, 51). However, significant heterogeneity in endothelial Tie2 expression was observed in clinical specimen from a variety of human cancers (Fathers et al. Am. J. Path. 2005, 167, 1753).
  • Tie2 and angiopoietins were found to be highly expressed in the cytoplasm of human colorectal adenocarcinoma cells indicating at the potential presence of an autocrine/paracrine growth loop in certain cancers (Nakayama et al. World J. Gastroenterol. 2005, 11, 964).
  • a similar autocrine/paracrine Ang1-Ang2-Tie2 loop was postulated for certain human gastric cancer cell lines (Wang et al. Biochem. Biophys. Res. Comm. 2005, 337, 386).
  • Ang1-Tie2 signalling axis The relevance of the Ang1-Tie2 signalling axis was challenged with various biochemical techniques. Inhibition of Ang1 expression by an antisense RNA approach resulted in decreased xenograft tumour growth (Shim et al. Int. J. Canc. 2001, 94, 6; Shim et al. Exp. Cell Research 2002, 279, 299). However, other studies report that experimental overexpression of Ang1 in tumour models leads to decreased tumour growth (Hayes et al. Br. J. Canc. 2000, 83, 1154; Hawighorst et al. Am. J. Pathol. 2002, 160, 1381; Stoeltzing et al. Cancer Res. 2003, 63, 3370).
  • Gene therapy by adenoviral vector delivered sTie2 was capable of reducing tumour growth rates of a murine mammary carcinoma and a murine melanoma and resulted in reduction of metastasis formation (Lin et al. Proc. Natl. Acad. Sci. USA 1998, 95, 8829). Similar effects were observed with related sTie2 constructs (Sieffle et al. Cancer Res. 1999, 59, 3185) and a Tek-Fc construct (Fathers et al. Am. J. Path. 2005, 167, 1753).
  • Adenovirus-delivered anti-Tie2 intrabodies were shown to inhibit growth of a human Kaposi's sarcoma and a human colon carcinoma upon peritumoural administration (Popkov et al. Cancer Res. 2005, 65, 972). Histopathological analysis revealed a marked decrease in vessel density in treated vs. control tumours. Phenotypic simultaneous knockout of KDR and Tie2 by an adenovirus delivered intradiabody resulted in significantly higher growth inhibition of a human melanoma xenograft model than KDR knockout alone (Jendreyko et al. Proc. Natl. Acad. Sci. USA 2005, 102, 8293).
  • the bispecific Tie2-KDR intradiabody was more active in an in vitro EC tube formation inhibition assay than the two monospecific intrabodies alone (Jendreyko et al. J. Biol. Chem. 2003, 278, 47812).
  • Systematic treatment of tumour-bearing mice with Ang2-blocking antibodies and peptide-Fc fusion proteins led to tumour stasis and elimination of tumour burden in a subset of animals (Oliner et al. Cancer Cell 2004, 6, 507).
  • small molecule inhibitors of the Tie2 kinase will be as efficacious in inhibiting angiogenesis as e.g. ligand antibodies, soluble decoy receptors or receptor intrabodies.
  • angiogenesis e.g. ligand antibodies, soluble decoy receptors or receptor intrabodies.
  • inhibition of Tie2 signalling alone might not be sufficient to induce an adequate antiangiogenic effect.
  • Simultaneous inhibition of several angiogenesis relevant signalling pathways could overcome such inadequacies.
  • novel chemotypes for small mocule inhibitors of the Tie2 kinase Fine tuning of additive anti-angiogenic activities as well as pharmacokinetic parameters such as e.g. solubility, membrane permeability, tissue distribution and metabolism will finally allow for chosing compounds of accurate profiles for various diseases caused by or associated with dysregulated vascular growth.
  • Avastin (Bevacizumab), a VEGF neutralizing antibody, blocks KDR and VEGFR1 signalling and has been approved for first-line treatment of metastatic colorectal cancer.
  • the small molecule multi-targeted kinase inhibitor Nexavar (Sorafenib) inhibits inter alia members of the VEGFR family and has been approved for the treatment of advanced renal cell carcinoma.
  • Sutent (Sunitinib), another multi-targeted kinase inhibitor with activity vs. VEGFR family members, has been approved by the FDA for treatment of patients with gastrointestinal stromal tumours (GIST) or advanced kidney tumours.
  • GIST gastrointestinal stromal tumours
  • Several other small molecule inhibitors of angiogenesis-relevant targets are in clinical and pre-clinical development.
  • AMG-386 an angiopoietin-targeting recombinant Fc fusion protein
  • ABT-869, GW697465A and A-422885.88 BSF466895
  • Pyrazolopyridines have been disclosed as antimicrobiotic substances (e.g. Attaby et al., Phosphorus, Sulphur and Silicon and the related Elements 1999, 149, 49-64; Goda et al. Bioorg. Med. Chem. 2004, 12, 1845).
  • a single 3-amino-1H-pyrazolo[3,4-b]pyridine with modest EGFR inhibitory activity has been published by Cavasotto et al. ( Bioorg. Med. Chem. Lett. 2006, 16, 1969).
  • 5-aryl-1H-3-aminopyrazolo[3,4-b]pyridines have been reported as GSK-3 inhibitors (Witherington et al. Bioorg. Med. Chem. Lett. 2003, 13, 1577).
  • WO 2003068773 discloses 3-acylaminopyrazolopyridine derivatives as GSK-3 inhibitors.
  • U.S. Pat. No. 4,224,322 U.S. Pat. No. 4,260,621 and DE2643753 further disclose 3-Amino-pyrazolo[3,4-b]pyridines as antithrombotic substances.
  • U.S. Pat. No. 5,478,830 further discloses fused heterocycles for the treatment of atherosclerosis.
  • WO 2001019828 discloses 125 templates, including 3-amino-1H-pyrazolopyridines, as modulators of the activity of receptor and non-receptor tyrosine and serine/threonine kinases.
  • WO 2002024679 discloses tetrahydropyridine-substituted pyrazolopyridines as IKK inhibitors.
  • WO 2004076450 further discloses 5-heteroaryl-pyrazolopyridines as p38 inhibitors.
  • WO 2004113304 discloses indazoles, benzisoxazoles and benzisothiazoles as inhibitors of protein tyrosine kinases, particularly of KDR kinase.
  • an exemplary compound from this patent (termed Abt-869; see above) is reported to be ⁇ 40 times less active against Tie2 vs. KDR in enzymatic assays and even ⁇ 1000 times less active against Tie2 than KDR in cellular assays (Albert et al. Mol. Cancer Ther. 2006, 5, 995).
  • WO 2006/050109 discloses pyrazolopyridines as protein tyrosine kinase inhibitors, particularly as KDR kinase inhibitors.
  • Such pharmacological profiles are highly desirable for treating diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, in particular solid tumours and metastases thereof, and also for treating non-oncological diseases of dysregulated vascular growth or non-oncological diseases which are accompanied with dysregulated vascular growth, such as retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel, diseases such as coronary and peripheral artery disease.
  • diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth in particular solid tumours and metastases thereof
  • non-oncological diseases of dysregulated vascular growth or non-oncological diseases which are accompanied with dysregulated vascular growth such as retinopathy,
  • the present invention thus relates to compounds of general formula (I):
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which
  • R 3 is selected from the group comprising, preferably consisting of, hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, hydroxy, amino, halogen, cyano;
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which:
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which:
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which:
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which:
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which
  • R a , R b , R c , R d1 , R d2 or R 8 when one or more of R a , R b , R c , R d1 , R d2 or R 8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 , R d2 or R 8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 , R d2 or R 8 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • the present invention relates to compounds of general formula (I), in which
  • R a , R b , R c , R d1 or R d2 when one or more of R a , R b , R c , R d1 or R d2 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said R a , R b , R c , R d1 or R d2 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of R a , R b , R c , R d1 or R d2 within a single molecule to be identical or different.
  • R a when R a is present twice in the molecule, then the meaning of the first R a may be H, for example, and the meaning of the second R a may be methyl, for example.
  • alkyl is to be understood as preferably meaning branched and unbranched alkyl, meaning e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl and decyl and the isomers thereof.
  • haloalkyl is to be understood as preferably meaning branched and unbranched alkyl, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen.
  • said haloalkyl is, e.g. chloromethyl, fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof.
  • alkoxy is to be understood as preferably meaning branched and unbranched alkoxy, meaning e.g. methoxy, ethoxy, propyloxy, iso-propyloxy, butyloxy, iso-butyloxy, tert-butyloxy, sec-butyloxy, pentyloxy, iso-pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy and the isomers thereof.
  • haloalkoxy is to be understood as preferably meaning branched and unbranched alkoxy, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen, e.g. chloromethoxy, fluoromethoxy, pentafluoroethoxy, fluoropropyloxy, difluoromethyloxy, trichloromethoxy, 2,2,2-trifluoroethoxy, bromobutyloxy, trifluoromethoxy, iodoethoxy, and isomers thereof.
  • halogen e.g. chloromethoxy, fluoromethoxy, pentafluoroethoxy, fluoropropyloxy, difluoromethyloxy, trichloromethoxy, 2,2,2-trifluoroethoxy, bromobutyloxy, trifluoromethoxy, iodoethoxy, and isomers thereof.
  • cycloalkyl is to be understood as preferably meaning a C 3 -C 10 cycloalkyl group, more particularly a saturated cycloalkyl group of the indicated ring size, meaning e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl group; and also as meaning an unsaturated cycloalkyl group containing one or more double bonds in the C-backbone, e.g.
  • a C 3 -C 10 cycloalkenyl group such as, for example, a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the linkage of said cyclolaklyl group to the rest of the molecule can be provided to the double or single bond.
  • heterocycloalkyl is to be understood as preferably meaning a C 3 -C 10 cycloalkyl group, as defined supra, featuring the indicated number of ring atoms, wherein one or more ring atom(s) is (are) (a) heteroatom(s) such as NH, NR d1 , O, S, or (a) group(s) such as a C(O), S(O), S(O) 2 , or, otherwise stated, in a C n -cycloalkyl group, (wherein n is an integer of 3, 4, 5, 6, 7, 8, 9, or 10), one or more carbon atom(s) is (are) replaced by said heteroatom(s) or said group(s) to give such a C n cycloheteroalkyl group.
  • said C n cycloheteroalkyl group refers, for example, to a three-membered heterocycloalkyl, expressed as C 3 -heterocycloalkyl, such as oxiranyl (C 3 ).
  • heterocycloalkyls are oxetanyl (C 4 ), aziridinyl (C 3 ), azetidinyl (C 4 ), tetrahydrofuranyl (C 5 ), pyrrolidinyl (C 5 ), morpholinyl (C 6 ), dithianyl (C 6 ), thiomorpholinyl (C 6 ), piperidinyl (C 6 ), tetrahydropyranyl (C 6 ), piperazinyl (C 6 ), trithianyl (C 6 ) and chinuclidinyl (C 8 ).
  • halogen or “Hal” is to be understood as preferably meaning fluorine, chlorine, bromine, or iodine.
  • alkenyl is to be understood as preferably meaning branched and unbranched alkenyl, e.g. a vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, or 2-methyl-prop-1-en-1-yl group.
  • alkynyl is to be understood as preferably meaning branched and unbranched alkynyl, e.g. an ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, or but-3-yn-1-yl group.
  • aryl is defined in each case as having 3-14 carbon atoms, preferably 6-12 carbon atoms, such as, for example, cyclopropenyl, phenyl, tropyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc, phenyl being preferred.
  • heteroaryl is understood as meaning an aromatic ring system which comprises 3-16 ring atoms, preferably 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed.
  • heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, etc.; or azocinyl, indoliziny
  • alkylene as used herein in the context of the compounds of general formula (I) is to be understood as meaning an optionally substituted alkyl chain or “tether”, having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted —CH 2 — (“methylene” or “single membered tether” or e.g.
  • alkylene tether is 1, 2, 3, 4, or 5 carbon atoms, more preferably 1 or 2 carbon atoms.
  • cycloalkylene as used herein in the context of the compounds of general formula (I) is to be understood as meaning an optionally substituted cycloalkyl ring, having 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3, 4, 5, or 6, carbon atoms, i.e. an optionally substituted cyclopropyl, cyclobutyl, cyclopenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl ring, preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • heterocycloalkylene as used herein in the context of the compounds of general formula (I) is to be understood as meaning a cycloalkylene ring, as defined supra, but which contains at least one heteroatom which may be identical or different, said heteroatom being such as O, N, S, S(O) or S(O) 2 .
  • arylene as used herein in the context of the compounds of general formula (I) which include the groups D and E, is to be understood as meaning an optionally substituted monocyclic or polycyclic arylene aromatic system e.g. arylene, naphthylene and biarylene, preferably an optionally substituted phenyl ring or “tether”, having 6 or 10 carbon atoms. More preferably, said arylene tether is a ring having 6 carbon atoms. If the term “arylene” is used it is to be understood that the linking residues can be arranged to each other in ortho-, para- and meta-position, e.g. an optionally substituted moiety of structure
  • heteroarylene as used herein in the context of the compounds of general formula (I) which include the groups D and E, is to be understood as meaning an optionally substituted monocyclic or polycyclic heteroarylene aromatic system, e.g. heteroarylene, benzoheteroarylene, preferably an optionally substituted 5-membered heterocycle, such as, for example, furan, pyrrole, thiazole, oxazole, isoxazole, or thiophene or “tether”, or a 6-membered heterocycle, such as, for example, pyridine, pyrimidine, pyrazine, pyridazine.
  • said heteroarylene tether is a ring having 6 carbon atoms, e.g. an optionally substituted structure as shown supra for the arylene moieties, but which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur. If the term “heteroarylene” is used it is to be understood that the linking residues can be arranged to each other in ortho-, para- and meta-position.
  • C 1 -C 6 As used herein, the term “C 1 -C 6 ”, as used throughout this text, e.g. in the context of the definition of “C 1 -C 6 -alkyl”, or “C 1 -C 6 -alkoxy”, is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 1 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g.
  • C 2 -C 6 as used throughout this text, e.g. in the context of the definitions of “C 2 -C 6 -alkenyl” and “C 2 -C 6 -alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 2 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g. C 2 -C 6 , C 3 -C 5 , C 3 -C 4 , C 2 -C 3 , C 2 -C 4 , C 2 -C 5 ; preferably C 2 -C 3 .
  • C 3 -C 10 As used herein, the term “C 3 -C 10 ”, as used throughout this text, e.g. in the context of the definitions of “C 3 -C 10 -cycloalkyl” or “C 3 -C 10 -heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C 3 -C 10 ” is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 10 , C 4 -C 9 , C 5 -C 8 , C 6 -C 7 ; preferably C 3 -C 6 .
  • C 3 -C 6 As used herein, the term “C 3 -C 6 ”, as used throughout this text, e.g. in the context of the definitions of “C 3 -C 6 -cycloalkyl” or “C 3 -C 6 -heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C 3 -C 6 ” is to be interpreted as any sub-range comprised therein, e.g. C 3 -C 4 , C 4 -C 6 , C 5 -C 6 .
  • C 6 -C 11 As used herein, the term “C 6 -C 11 ”, as used throughout this text, e.g. in the context of the definitions of “C 6 -C 11 -aryl”, is to be understood as meaning an aryl group having a finite number of carbon atoms of 5 to 11, i.e. 5, 6, 7, 8, 9, 10 or 11 carbon atoms, preferably 5, 6, or 10 carbon atoms. It is to be understood further that said term “C 6 -C 11 ” is to be interpreted as any sub-range comprised therein, e.g. C 5 -C 10 , C 6 -C 9 , C 7 -C 8 ; preferably C 5 -C 6 .
  • C 5 -C 10 As used herein, the term “C 5 -C 10 ”, as used throughout this text, e.g. in the context of the definitions of “C 5 -C 10 -heteroaryl”, is to be understood as meaning a heteroaryl group having a finite number of carbon atoms of 5 to 10, in addition to the one or more heteroatoms present in the ring i.e. 5, 6, 7, 8, 9, or 10 carbon atoms, preferably 5, 6, or 10 carbon atoms. It is to be understood further that said term “C 5 -C 10 ” is to be interpreted as any sub-range comprised therein, e.g. C 6 -C 9 , C 7 -C 8 , C 7 -C 8 ; preferably C 5 -C 6 .
  • C 1 -C 3 As used herein, the term “C 1 -C 3 ”, as used throughout this text, e.g. in the context of the definitions of “C 1 -C 3 -alkylene”, is to be understood as meaning an alkylene group as defined supra having a finite number of carbon atoms of 1 to 3, i.e. 1, 2, or 3. It is to be understood further that said term “C 1 -C 3 ” is to be interpreted as any sub-range comprised therein, e.g. C 1 -C 2 , or C 2 -C 3 .
  • the term “one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, three or four tines, more particularly one, two or three times, more particularly one or two times”.
  • isomers is to be understood as meaning chemical compounds with the same number and types of atoms as another chemical species. There are two main classes of isomers, constitutional isomers and stereoisomers.
  • substitutional isomers is to be understood as meaning chemical compounds with the same number and types of atoms, but they are connected in differing sequences. There are functional isomers, structural isomers, tautomers or valence isomers.
  • stereoisomers is to be understood as meaning chemical compounds having atoms which are connected sequentially in the same way, such that condensed formulae for two isomeric molecules are identical. The isomers differ, however, in the way the atoms are arranged in space. There are two major sub-classes of stereoisomers: conformational isomers, which interconvert through rotations around single bonds, and configurational isomers, which are not readily interconvertable.
  • Configurational isomers are, in turn, can be enantiomers and/or diastereomers.
  • Enantiomers are stereoisomers which are related to each other as mirror images. Enantiomers can contain any number of stereogenic centers, as long as each center is the exact mirror image of the corresponding center in the other molecule. If one or more of these centers differs in configuration, the two molecules are no longer mirror images.
  • Stereoisomers which are not enantiomers are called diastereomers.
  • Diastereomers which still have a different constitution are another sub-class of diastereomers, the best known of which are simple cis-trans isomers.
  • a suitably pharmaceutically acceptable salt of the pyrazolopyridines of the present invention may be, for example, an acid-addition salt of a pyrazolopyridine of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, para-toluenesulphonic, methylsulphonic, citric, tartaric, succinic or maleic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, para-toluenesulphonic, methylsulphonic, citric, tartaric, succinic or maleic acid.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol.
  • the compound according to Formula (I) can exist as N-oxides which are defined in that at least one nitrogen of the compounds of the general Formula (I) may be oxidized.
  • the compound according to Formula (I) can exist as solvates, in particular as hydrate, wherein the compound according to Formula (I) may contain polar solvents, in particular water, as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or unstoichiometric ratio.
  • stoichiometric solvates e.g. hydrate
  • the compounds of the present invention according to Formula (I) can exist as prodrugs, e.g. as in vivo hydrolysable esters.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound of formula (I) containing a carboxy or hydroxyl group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C 1 -C 6 alkoxymethyl esters, e.g.
  • C 1 -C 6 alkanoyloxymethyl esters e.g. pivaloyloxymethyl, phthalidyl esters, C 3 -C 8 cycloalkoxy-carbonyloxy-C 1 -C 6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1 -C 6 -alkoxycarbonyloxyethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound of formula (I) containing a hydroxyl group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxyl group.
  • Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxyl include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the compounds of the present invention according to Formula (I), or salts, N-oxides, or prodrugs thereof, may contain one or more asymmetric centers.
  • Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
  • Preferred stereoisomers are those with the configuration which produces the more desirable biological activity.
  • Separated, pure or partially purified configurational isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
  • the compounds of the present invention can be used in treating diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth. Especially, the compounds effectively interfere with Tie2 signalling. In addition, the compounds of the present invention allow for tunability of the inhibition of an additional kinase target according to the appropriate therapeutic needs.
  • another aspect of the present invention is a use of the compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth.
  • the use is in the treatment of diseases, wherein the diseases are tumours and/or metastases thereof.
  • diseases are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
  • diseases are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
  • a further use is in the treatment of diseases, wherein the diseases are coronary and peripheral artery disease.
  • diseases are ascites, oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma, chronic lung disease, adult respiratory distress syndrome, bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
  • oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma
  • chronic lung disease such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometri
  • Yet another aspect of the invention is a method of treating a disease of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, by administering an effective amount of a compound of general formula (I) described supra.
  • the diseases of said method is tumour and/or metastases thereof.
  • the diseases of said method are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, e.g. rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
  • retinopathy other angiogenesis dependent diseases of the eye
  • cornea transplant rejection or age-related macular degeneration e.g. rheumatoid arthritis
  • other inflammatory diseases associated with angiogenesis in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
  • the disease of the method are coronary and peripheral artery disease.
  • oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma, chronic lung disease, adult respiratory distress syndrome, bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
  • oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma
  • chronic lung disease such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-
  • the compounds of the present invention can thus be applied for the treatment of diseases accompanied by neoangiogenesis.
  • diseases accompanied by neoangiogenesis This holds principally for all solid tumours, e.g. breast, colon, renal, lung and/or brain tumours or metastases thereof and can be extended to a broad range of diseases, where pathologic angiogenesis is persistent.
  • pathologic angiogenesis This applies for diseases with inflammatory association, diseases associated with oedema of various forms and diseases associated with stromal proliferation and pathologic stromal reactions broadly.
  • Particularly suited is the treatment for gynaecological diseases where inhibition of angiogenic, inflammatory and stromal processes with pathologic character can be inhibited.
  • the treatment is therefore an addition to the existing armament to treat diseases associated with neoangiogenesis.
  • the compounds of the present invention can be used in particular in therapy and prevention of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment if the tumour growth is accompanied with persistent angiogenesis.
  • tumour therapy is not restricted to tumour therapy but is also of great value for the treatment of other diseases with dysregulated vascular growth.
  • This includes retinopathy and other angiogenesis dependent diseases of the eye (e.g. cornea transplant rejection, age-related macular degeneration), rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis such as psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke and inflammatory diseases of the bowel, such as Crohn's disease.
  • oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma.
  • disease states such as ascites, oedema, such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma.
  • chronic lung disease adult respiratory distress syndrome.
  • benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation. It is therapeutically valuable for the treatment of diseases, where deposition of fibrin or extracellular matrix is an issue and stroma proliferation is accelerated (e.g. fibrosis, cirrhosis, carpal tunnel syndrome etc).
  • Another aspect of the present invention is a pharmaceutical composition which contains a compound of Formula (I) or pharmaceutically acceptable salts thereof, N-oxides, solvates, hydrates, isomers or mixtures of isomers thereof, in admixture with one or more suitable excipients.
  • This composition is particularly suited for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth as explained above.
  • the compounds or mixtures thereof may be provided in a pharmaceutical composition, which, as well as the compounds of the present invention for enteral, oral or parenteral application contain suitably pharmaceutically acceptable organic or inorganic inert base material, e.g. purified water, gelatin, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
  • suitably pharmaceutically acceptable organic or inorganic inert base material e.g. purified water, gelatin, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
  • compositions of the present invention may be provided in a solid form, e.g. as tablets, dragées, suppositories, capsules or in liquid form, e.g. as a solution, suspension or emulsion.
  • the pharmaceutical composition may additionally contain auxiliary substances, e.g. preservatives, stabilisers, wetting agents or emulsifiers, salts for adjusting the osmotic pressure or buffers.
  • sterile injection solutions or suspensions are preferred, especially aqueous solutions of the compounds in polyhydroxyethoxy containing castor oil.
  • compositions of the present invention may further contain surface active agents, e.g. salts of gallenic acid, phosphorlipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof.
  • surface active agents e.g. salts of gallenic acid, phosphorlipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof.
  • dragées or capsules with talcum and/or hydrocarbon-containing carriers and binders are preferred.
  • Further application in liquid form is possible, for example as juice, which contains sweetener if necessary.
  • the dosage will necessarily be varied depending upon the route of administration, age, weight of the patient, the kind and severity of the illness being treated and similar factors.
  • the daily dose is in the range of 0.5 to 1,500 mg.
  • a dose can be administered as unit dose or in part thereof and distributed over the day. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • compounds of general formula (I) of the present invention can be used alone or, indeed in combination with one or more further drugs, particularly anti-cancer drugs or compositions thereof.
  • said combination it is possible for said combination to be a single pharmaceutical composition entity, e.g. a single pharmaceutical formulation containing one or more compounds according to general formula (I) together with one or more further drugs, particularly anti-cancer drugs, or in a form, e.g. a “kit of parts”, which comprises, for example, a first distinct part which contains one or more compounds according to general formula I, and one or more further distinct parts each containing one or more further drugs, particularly anti-cancer drugs. More particularly, said first distinct part may be used concomitantly with said one or more further distinct parts, or sequentially.
  • Another aspect of the present invention is a method which may be used for preparing the compounds according to the present invention.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH 2 silica gel in combination with a Flashmaster II autopurifier (Argonaut/Biotage) and eluants such as gradients of hexane/EtOAc or DCM/ethanol.
  • chromatography particularly flash column chromatography
  • Separtis such as Isolute® Flash silica gel or Isolute® Flash NH 2 silica gel in combination with a Flashmaster II autopurifier (Argonaut/Biotage) and eluants such as gradients of hexane/EtOAc or DCM/ethanol.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluants such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluants such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid or aqueous ammonia.
  • pyridones 3 are transformed into pyridines of general formula 4 carrying a leaving group X at the C2 position, wherein X stands for, but is not limited to, trifluoromethanesulfonyl (OTf), acetate (OAc), methoxy (OMe), Cl or F.
  • OTf trifluoromethanesulfonyl
  • OAc acetate
  • OMe methoxy
  • F X stands for Cl
  • Conversion of intermediate compounds of general formula 3 into intermediates of general formula 4 may be achieved by a variety of methods, e.g.
  • Intermediate compounds of general formula 6 are formed from intermediate compounds of general formula 5 by reaction with, for example, a suitably functionalized carboxylic acid or acid chloride (leading to carboxylic amides), or a suitably functionalized sulfonyl chloride (leading to sulfonamides), in the presence of a suitable base as necessary, e.g. pyridine, which may also be used as solvent, optionally in the presence of an inert solvent, e.g. dichloromethane, acetonitrile, DMF or THF, at temperatures ranging from ⁇ 20° C. to the boiling point of the solvent, whereby room temperature is preferred.
  • a suitable base e.g. pyridine
  • an inert solvent e.g. dichloromethane, acetonitrile, DMF or THF
  • the corresponding acid which may be obtained from the corresponding ester by saponification, can be reacted with amines of general formula 5 in aprotic polar solvents, such as, for example, DMF, via an activated acid derivative, which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide (DIC), at temperatures of between 0° C.
  • aprotic polar solvents such as, for example, DMF
  • an activated acid derivative which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide (DIC), at temperatures of between 0° C.
  • aprotic polar solvents such as, for example, DMF
  • an activated acid derivative which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcar
  • reagents such as, for example, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (see for example Chem. Comm. 1994, 201), at temperatures of between 0° C.
  • HATU O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • DCC dicyclohexylcarbodiimid
  • DMAP dimethylaminopyridine
  • EDCI N-ethyl-N′-dimethylaminopropylcarbodiimide
  • T3P T3P
  • a suitable base such as N-methylmorpholine, for example, may be necessary.
  • Amide formation may also be accomplished via the acid halide, mixed acid anhydride, imidazolide or azide.
  • carboxylic acids required for the amide coupling reactions above described are either commercially available or are accessible from commercially available carboxylic esters or nitriles.
  • (hetero)aryls bearing a methylenenitrile substituent are easily accessible from the respective halides via a nucleophilic substitution reaction (e.g. KCN, cat. KI, EtOH/H 2 O).
  • Benzylic nitrites and esters can be efficiently alkylated at the benzylic position under basic conditions and subsequently hydrolyzed to the corresponding alkylated acids.
  • Conditions for ⁇ -alkylations of nitrites and esters include, but are not limited to, the use of alkyl bromides or alkyl iodides as electrophiles under basic conditions in the presence or absence of a phase-transfer catalyst in a mono- or biphasic solvent system. Particularly, by using excess alkyl iodides as electrophilic species ⁇ , ⁇ -dialkylated nitrites are accessible.
  • cycloalkyl moieties can be installed at the benzylic position of nitrites and esters ( J. Med. Chem. 1975, 18, 144; WO2003022852).
  • the hydrolysis of nitrites to yield carboxylic acids can be accomplished, as known to the person skilled in the art, under acid or base-mediated conditions.
  • the more particular synthesis of substituted 1-Phenylcyclopropylcarboxylic acids is described in the following scheme (Scheme 2).
  • a variety of substituted hydrazine building blocks required e.g. for the conversion of pyridines 6 into compounds of the general formula (I) is commercially available, either in form of their free base or as various types of salts (e.g. hydrochlorides, oxalates), which can be transformed into their respective free bases by alkaline treatment either before the cyclization or in situ.
  • salts e.g. hydrochlorides, oxalates
  • substituted alkyl-, allyl-, and benzylhydrazines are accessible from the respective alkyl-, allyl- and benzylhalides, preferably the respective alkyl-, allyl- and benzylbromides, by nucleophilic substitution reaction with a protected hydrazine, e.g. BocNHNH 2 , in an inert solvent, preferably MeOH, in the presence of an amine promoter, e.g.
  • the substituents R a , R 1 , R 2 , R 3 , R 4 , R 5 may be further modified on each step (general formula 1 to general formula 13) or in the last step (general formula I). These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, substitution or other reactions. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999).
  • the 3-amino group of the pyrazole nucleus leads to compounds of the general formula 8.
  • Suitable protecting groups for amino functions are well known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3 rd edition, Wiley 1999).
  • the 3-amino group is protected by formation of the respective phthalimide.
  • phthalimido protection of 3-aminopyrazoles can be achieved by reaction of the amine with phthalic anhydride in a suitable inert solvent, e.g. acetonitrile or dioxane, optionally in the presence of a basic mediator, e.g. Et 3 N, DIPEA or DMAP, at temperatures from room temperature up to the boiling point of the respective solvent.
  • a suitable inert solvent e.g. acetonitrile or dioxane
  • a basic mediator e.g. Et 3 N, DIPEA or DMAP
  • Nitro reduction yielding amino compounds of the general formula 9 and e.g. sulfonamide or amide formation to give compounds of general formula 10 are feasible as described above.
  • the compounds of the present invention (I) are accessible by deprotection of the amino group in compounds of the general formula 10.
  • cleavage of the phthalimido group can be achieved, as known to the person skilled in the art, by reaction with hydrazine or hydrazine hydrate in solvents such as EtOH at temperatures from room temperature up to the boiling point of the respective solvent.
  • R 1 -substituents as present in compounds of the present invention of general formula I can be accomplished after formation of 1H-pyrazolopyridines 11 by subsequent acylation or alkylation (Scheme 4). This process is of particular importance if the appropriately substituted hydrazines are not readily available.
  • 1H-Pyrazolopyridines of general formula 11 are accessible from synthetic intermediates of formula 6 (which can be prepared as described above) by cyclization with hydrazine or more preferably with hydrazine hydrate in a suitable solvent, preferably 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred.
  • Conditions for N1-alkylation of 3-aminopyrazoles of the general formula 11 include, but are not limited to, treatment with an excess of the respective electrophile (e.g. alkyl-, allyl-, benzylhalides or ⁇ -halocarbonyl compounds) in the presence of a base, e.g. potassium carbonate or cesium carbonate, in DMF at temperatures from room temperature up to the boiling point of the solvent.
  • a base e.g. potassium carbonate or cesium carbonate
  • 1H-pyrazoles of general formula 11 are deprotonated with sodium hydride in DMF at temperatures from 0° C. up to 80° C. followed by reaction with the respective electrophile (e.g. alkyl-, allyl-, benzylhalides or ⁇ -halocarbonyl compounds) in DMF at temperatures from room temperature up to the boiling point of the solvent.
  • electrophile e.g. alkyl-, allyl-, benzylhalides or ⁇ -halocarbonyl compounds
  • Scheme 6 depicts the more specific synthesis of pyridones of formula 3a, which in turn may be used as substrates in those conversions described above, especially those in Scheme 1.
  • methyl ketone 2a may be used in the conversion shown in Scheme 5 replacing substrate 2.
  • Methyl ketone 2a is either commercially available or accessible from the corresponding ⁇ -ketoester by alkylation by various conditions known to the person skilled in the art, for example analogous to those described in US20030065212 and U.S. Pat. No. 5,286,723 and those described above.
  • the ethyl ester functionality in substrate 2a, in pyridone 3a and subsequent products may be further modified.
  • the respective aniline (1 eq.) was dissolved in DCM (12 mL per mmol aniline) and treated with pyridine (1.5 eq.) and the respective carboxylic acid chloride (1.2 eq.; prepared from the respective carboxylic acid by treatment with thionyl chloride and subsequent concentration in vacuo).
  • the reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting aniline (usually 16 h).
  • the reaction mixture was quenched with NaHCO 3 and extracted with ethyl acetate. The organic layers were dried and concentrated in vacuo. In most cases, the crude amide was used in the subsequent cyclization without further purification, however, in cases with incomplete amide formation (as judged by TLC) flash column chromatography was applied for purification.
  • Dimethylformamide dimethyl acetal (10 ml, 72.8 mmol) was added to the suspension of the product from step 1 (13.0 g, 61 mmol) and AcOH (4.4 ml, 72.8 mmol). The mixture was heated until it began to boil. After cooling, 25 ml of isopropanol was added to the mixture, it was filtered, washed with isopropanol and dried. 13.0 g of crude product containing 85% of the desired enamine was obtained.
  • Non-commercial carboxylic acid derivatives were prepared as exemplified below:
  • the following example compounds 1 to 13 were prepared by applying GP 4 or GP 5 using the respective aniline intermediates as resulting from GP 3, the respective carboxylic acid chlorides or sulfonyl chlorides and subsequently methyl hydrazine for cyclization.
  • exemplary compounds 14 to 65 of the present invention are accessible applying procedures described above using the respective aniline intermediates, as resulting from GP 3, via amide or sulfonamide formation as exemplified above, followed by cyclization with substituted hydrazines.
  • said amide or sulfonamide formation may be followed by cyclization with e.g. 80% hydrazine hydrate, and R 1 is introduced in the final step e.g. by alkylation, (compare to GP 4, 5, 6a, 6b and 7):
  • CHO cell-cultures which are stably transfected by known techniques with Tie2 using DHFR deficiency as selection marker, are stimulated by angiopoietin-2.
  • the specific autophosphorylation of Tie2 receptors is quantified with a sandwich-ELISA using anti-Tie2 antibodies for catch and anti-phosphotyrosine antibodies coupled to HRP for detection.
  • Tie2-inhibitory activity of compounds of the present invention was quantified employing two Tie2 HTRF assay as described in the following paragraphs.
  • a recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by Glutathion-Sepharose affinity chromatography was used as kinase.
  • GST-Tie2-fusion protein Upstate Biotechnology, Dundee, Scotland
  • biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG C-terminus in amid form
  • Detection of phosphorylated product is achieved specifically by a trimeric detection complex consisting of the phosphorylated substrate, streptavidin-XLent (SA-XLent) which binds to biotin, and Europium Cryptate-labeled anti-phosphotyrosine antibody PT66 which binds to phosphorylated tyrosine.
  • SA-XLent streptavidin-XLent
  • PT66 Europium Cryptate-labeled anti-phosphotyrosine antibody
  • Tie-2 (3.5 ng/measurement point) was incubated for 60 min at 22° C. in the presence of 10 ⁇ M adenosine-tri-phosphate (ATP) and 1 ⁇ M substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH 2 ) with different concentrations of test compounds (0 ⁇ M and concentrations in the range 0.001-20 ⁇ M) in 5 ⁇ l assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl 2 , 0.5 mM MnCl 2 , 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide].
  • ATP adenosine-tri-phosphate
  • substrate peptide biotin-Ahx-EPKDDAYPLYSDFG-NH 2
  • the reaction was stopped by the addition of 5 ⁇ l of an aqueous buffer (25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.2 ⁇ M, from Cis Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3 ng/ ⁇ l; a europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer).
  • an aqueous buffer 25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin
  • EDTA 90 mM
  • HTRF Homogeneous Time Resolved Fluorescence detection reagents streptavidine-XLent (0.2 ⁇ M, from Cis Biointernational, Marcoule, France) and PT
  • the resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • a Rubystar Rubystar
  • Viewlux Perkin-Elmer
  • the ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate peptide.
  • a recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by Glutathion-Sepharose affinity chromatography was used as kinase.
  • As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany).
  • Tie-2 was incubated at a conc. 12.5 ng/ ⁇ l of for 20 min at 22° C. in the presence of 250 ⁇ M adenosine-tri-phosphate (ATP) in assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl 2 , 0.5 mM MnCl 2 , 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml)].
  • ATP adenosine-tri-phosphate
  • the preactivated Tie-2 (0.5 ng/measurement point) was incubated for 20 min at 22° C. in the presence of 10 ⁇ M adenosine-tri-phosphate (ATP) and 1 ⁇ M substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH 2 ) with different concentrations of test compounds (0 ⁇ M and concentrations in the range 0.001-20 ⁇ M) in 5 ⁇ l assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl 2 , 0.5 mM MnCl 2 , 0.1 mM sodium ortho-vanadate, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide].
  • ATP adenosine-tri-phosphate
  • substrate peptide biotin-Ahx
  • the reaction was stopped by the addition of 5 ⁇ l of an aqueous buffer (25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.2 ⁇ M, from Cis Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3 ng/ ⁇ l; a europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer).
  • an aqueous buffer 25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin
  • EDTA 90 mM
  • HTRF Homogeneous Time Resolved Fluorescence detection reagents streptavidine-XLent (0.2 ⁇ M, from Cis Biointernational, Marcoule, France) and PT
  • the resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • a Rubystar Rubystar
  • Viewlux Perkin-Elmer
  • the ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate peptide.
  • c-Kit-inhibitory activity of compounds of the present invention was quantified employing the c-kit HTRF assay as described in the following paragraphs.
  • GST-tagged recombinant kinase domain of the human c-kit expressed in SF-9 cells was used as kinase.
  • As substrate for the kinase reaction biotinylated poly-(Glu, Tyr) (Cis biointernational, France) was used.
  • c-Kit was incubated for 30 min at 22° C. in the presence of different concentrations of test compounds in 5 ⁇ l assay buffer [50 mM Hepes/NaOH pH 7.0, 1 mM MgCl 2 , 5 mM MnCl 2 , 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 10 ⁇ M adenosine-tri-phosphate (ATP), 1.3 ⁇ g/ml substrate, 0.001% (v/v) Nonidet-P40 (Sigma), 1% (v/v) dimethylsulfoxide].
  • the concentration of c-kit was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range.
  • the reaction was stopped by the addition of 5 ⁇ l of a solution of HTRF detection reagents (0.1 ⁇ M streptavidine-XLent and 1 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer) in an aqueous EDTA-solution (80 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0).
  • HTRF detection reagents 0.1 ⁇ M streptavidine-XLent and 1 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer
  • the resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • a Rubystar Rubystar
  • Viewlux Perkin-Elmer
  • the ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate.

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Abstract

The invention relates to substituted arylpyrazolopyridines according to the general formula (I):
Figure US07795264-20100914-C00001
in which A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the claims, and salts thereof, to pharmaceutical compositions comprising said substituted arylpyrazolopyridines, to methods of preparing said substituted arylpyrazolopyridines as well as the use thereof for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth, wherein the compounds effectively interfere with Tie2 signalling.

Description

This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/816,625, filed Jun. 27, 2006, which is incorporated by reference herein.
The present invention relates to substituted arylpyrazolopyridine compounds of general formula (I) and salts thereof, to pharmaceutical compositions comprising said substituted arylpyrazolopyridine compounds, to methods of preparing said substituted arylpyrazolopyridines as well as to the use thereof.
SCIENTIFIC BACKGROUND
Dysregulated vascular growth plays a critical role in a variety of inflammatory diseases, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, rheumatoid arthritis and inflammatory bowl disease. Aberrant vascular growth is also involved in neovascular ocular diseases such as age-related macular degeneration and diabetic retinopathy. Additionally, sustained vascular growth is accepted as one hallmark of cancer development (Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57). While tumours initially grow either as an avascular mass or by co-opting existing host vessels, growth beyond a few mm3 in size is depending on the induction of vessel neogrowth in order to sufficiently provide the tumour with oxygen and nutrients. Induction of angiogenesis is a prerequisite that the tumour surpasses a certain size (the so called angiogenic switch). An intricate signalling interaction network between cancer cells and the tumour microenvironment triggers the induction of vessel growth from existing vasculature. The dependence of tumours on neovascularization has led to a new treatment paradigm in cancer therapy (Ferrara et al. Nature 2005, 438, 967; Carmeliet Nature 2005, 438, 932). Blocking tumour neovascularization by small molecule or antibody-mediated inhibition of relevant signal transduction pathways holds a great promise for extending currently available therapy options.
The development of the cardiovascular system involves two basic stages. In the initial vasculogenesis stage, which only occurs during embryonal development, angioblasts differentiate into endothelial cells which subsequently form a primitive vessel network. The subsequent stage, termed angiogenesis, involves the remodeling of the initial vasculature and sprouting of new vessels (Risau, W. Nature 1997, 386, 671; Jain, R. K. Nat. Med. 2003, 9, 685). Physiologically, angiogenesis occurs in wound healing, muscle growth, the female cycle and in the above mentioned disease states.
It has been found that receptor tyrosine kinases of the vascular endothelial growth factor (VEGF) family and the Tie (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptor tyrosine kinases are essential for both developmental and disease-associated angiogenesis (Ferrara et al Nat. Med. 2003, 9, 669; Dumont et al. Genes Dev. 1994, 8, 1897; Sato et al. Nature 1995, 376, 70).
In adults the Tie2 receptor tyrosine kinase is selectively expressed on endothelial cells (EC) of the adult vasculature (Schlaeger et al. Proc. Nat. Acad. Sci. USA 1997, 94, 3058). Immunohistochemical analysis demonstrated the expression of Tie2 in adult rat tissues undergoing angiogenesis. During ovarian folliculogenesis, Tie2 is expressed in neovessels of the developing corpus luteum. Four endogeneous ligands—angiopoietins 1 to 4—have been identified for the type 1 transmembrane Tie2 (also named Tek) receptor, while no ligands have been identified so far for the Tie1 receptor. Binding of the extracellular Tie2 domain to the C-terminal fibrinogen-like domains of the various angiopoietins leads to significantly different cellular effects. In addition, heterodimerizations between Tie1 and Tie2 receptors have been postulated to influence ligand binding.
Binding of Ang1 to Tie2 expressed on EC induces receptor cross-phosphorylation and kinase activation thus triggering various intracellular signalling pathways. The intracellular C-terminal tail of the Tie2 protein plays a crucial role in Tie2 signalling (Shewchuk et al. Structure 2000, 8, 1105). Upon ligand binding, a conformational change is induced which removes the C-tail out of its inhibitory conformation thus allowing kinase activation by cross-phoshorylation of various Tyr residues in the C-tail, which subsequently function as docking sites for phosphotyrosine-binding (PTB) site possessing down-stream mediators. Cellular effects initiated by Ang1 activation of Tie2 include inhibition of EC apoptosis, stimulation of EC migration and blood vessel reorganization, suppression of inflammatory gene expression and suppression of vascular permeability (Brindle et al. Circ. Res. 2006, 98, 1014). In contrast to VEGF-VEGFR signalling in EC, Ang1 activation of Tie2 does not stimulate EC proliferation in the majority of published assay settings.
The anti-apoptotic effect of Tie2 signalling was shown to be mediated mainly by the PI3K-Akt signalling axis which is activated by binding of the regulatory p85 subunit of PI3K to Y1102 in the Tie2 C-tail (DeBusk et al. Exp. Cell. Res. 2004, 298, 167; Papapetropoulos et al. J. Biol. Chem. 2000, 275, 9102; Kim et al. Circ. Res. 2000, 86, 24). In contrast, the chemotactic response downstream of the activated Tie2 receptor requires crosstalk between PI3K and the adaptor protein Dok-R. Membrane localization of Dok-R via binding of its plekstrin homology (PH) domain to PI3K and simultaneous binding to Y1108 in the Tie2 C-tail via its PTB domain leads to Dok-R phoshorylation and downstream signalling via Nck and Pak-1 (Jones et al. Mol. Cell Biol. 2003, 23, 2658; Master et al. EMBO J. 2001, 20, 5919). PI3K-mediated recruitment of the adaptor protein ShcA to Y1102 of the Tie2 C-tail is also believed to induce cellular sprouting and motility effects involving activation of endothelial nitric oxide synthase (eNOS), focal adhesion kinase (FAK) and the GTPases RhoA and Rac1. Other downstream mediators of Tie2 signalling include the adaptor protein Grb2, which mediates Erk1/2 stimulation, and the SHP-2 phosphatase.
In conclusion, basal activation of the Tie2 pathway by Ang1 is believed to maintain quiescence and integrity of the endothelium of the adult vasculature by providing a cell survival signal for ECs and by maintaining the integrity of the EC lining of blood vessels (Peters et al. Recent Prog. Horm. Res. 2004, 59, 51).
In contrast to Ang1, Ang2 is not able to activate Tie2 on EC unless Ang2 is present in high concentration or for prolonged periods. However, Ang2 functions as a Tie2 agonist in non-endothelial cells tranfected with Tie2. The structural basis for this context-dependence of the Ang2-Tie2 interaction is to date not understood.
In endothelial cells, however, Ang2 functions as Tie2 antagonist and thus blocks the agonistic activity of Ang1 (Maisonpierre et al. Science 1997, 277, 55). Ang2 binding to Tie2 prevents Ang1-mediated Tie2 activation which leads to vessel destabilization and results in vessel regression in the absence of pro-angiogenic stimuli such as VEGF. While Ang1 is widely expressed by periendothelial cells in quiescent vasculature such as pericytes or smooth muscle cells, Ang2 expression occurs in areas of ongoing angiogenesis. Ang2 can be stored in Weibel-Palade bodies in the cytoplasm of EC allowing for a quick vascular response upon stimulation.
Ang1 and Ang2 are expressed in the corpus luteum, with Ang2 localizing to the leading edge of proliferating vessels and Ang1 localizing diffusively behind the leading edge. Ang2 expression is inter alia initiated by hypoxia (Pichiule et al. J. Biol. Chem. 2004, 279, 12171). Ang2 is upregulated in the tumour vasculature and represents one of the earliest tumour markers. In the hypoxic tumour tissue, Ang2 expression induces vessel permeability and—in the presence of e.g. pro-angiogenic VEGF—triggers angiogenesis. After VEGF mediated EC proliferation and vessel sprouting maturation of the newly formed vessels again necessitates Tie2 activation by Ang1. Therefore, a subtle balancing of Tie2 activity plays a pivotal role in the early as well as late stages of neovascularization. These observations render the Tie2 RTK an attractive target for anti-angiogenesis therapy in diseases caused by or associated with dysregulated vascular growth. However, it remains to be shown if targeting the Tie2 pathway alone will be sufficient to achieve efficacious blockade of neovascularization. In certain diseases or disease subtypes it might be necessary or more efficacious to block several angiogenesis-relevant signalling pathways simultaneously.
Various theories have been discussed to explain the differential effects of Ang1 and Ang2 on Tie2 downstream signalling events. Binding of Ang1 and Ang2 in a structurally different manner to the Tie2 ectodomain could induce ligand-specific conformational changes of the intracellular kinase domain explaining different cellular effects. Mutational studies however point toward similar binding sites of Ang1 and Ang2. In contrast, various publications have focussed on different oligomerization states of Ang1 vs. Ang2 as basis for different receptor multimerization states upon ligand binding. Only Ang1 present in its tetramer or higher-order structure initiates Tie2 activation in EC while Ang2 was reported to exist as a homodimer in its native state (Kim et al. J. Biol. Chem. 2005, 280, 20126; Davis et al. Nat. Struc. Biol. 2003, 10, 38; Barton et al. Structure 2005, 13, 825). Finally, specific interactions of Ang1 or Ang2 with additional cell-specific co-receptors could be responsible for the different cellular effects of Ang1 vs. Ang2 binding to Tie2. Interaction of Ang1 with integrin α5β1 has been reported to be essential for certain cellular effects (Carlson et al. J. Biol. Chem. 2001, 276, 26516; Dallabrida et al. Circ. Res. 2005, 96, e8). Integrin α5β1 associates constitutively with Tie2 and increases the receptor's binding affinity for Ang1 resulting in initiation of downstream signalling at lower Ang1 effector concentrations in situations where integrin α5β1 is present. The recently solved crystal structure of the Tie2-Ang2 complex suggests however that neither the oligomerization state nor a different binding mode causes the opposing cellular effects (Barton et al. Nat. Struc. Mol. Biol. 2006, advance online publication).
Ang1-Tie2 signalling plays also a role in the development of the lymphatic system and in lymphatic maintenance and sprouting (Tammela et al. Blood 2005, 105, 4642). An intimate cross-talk between Tie2 and VEGFR-3 signalling in lymphangiogenesis seems to equal the Tie2-KDR cross-talk in blood vessel angiogenesis.
A multitude of studies have underscored the functional significance of Tie2 signalling in the development and maintenance of the vasculature. Disruption of Tie2 function in Tie2−/− transgenic mice leads to early embryonic lethality between days 9.5 and 12.5 as a consequence of vascular abnormalities. Tie2−/− embryos fail to develop the normal vessel hierachy suggesting a failure of vascular branching and differentiation. The heart and vessels in Tie2−/− embryos show a decreased lining of EC and a loosened interaction between EC and underlying pericyte/smooth muscle cell matrix. Mice lacking functional Ang1 expression and mice overexpressing Ang2 display a phenotype reminiscent of the phenotype of Tie2−/− mice (Suri et al. Cell 1996, 87, 1171). Ang2−/− mice have profound defects in the growth and patterning of lymphatic vasculature and fail to remodel and regress the hyaloid vasculature of the neonatal lens (Gale et al. Dev. Cell 2002, 3, 411). Ang1 rescued the lymphatic defects, but not the vascular remodelling defects. Therefore, Ang2 might function as a Tie2 antagonist in blood vasculature but as a Tie2 agonist in developing lymph vasculature suggesting redundant roles of Ang1 and Ang2 in lymphatic development.
Aberrant activation of the Tie2 pathway is involved in various pathological settings. Activating Tie2 mutations leading to increased ligand-dependent and ligand-independent Tie2 kinase activity cause inherited venous malformations (Vikkula et al. Cell 1996, 87, 1181). Increased Ang1 mRNA and protein levels as well as increased Tie2 activation have been reported in patients with pulmonary hypertension (PH). Increased pulmonary arterial pressure in PH patients results from increased coverage of pulmonary arterioles with smooth muscle cells (Sullivan et al. Proc. Natl. Acad. Sci. USA 2003, 100, 12331). In chronic inflammatory diseases, like in psoriasis, Tie2 and the ligands Ang1 and Ang2 are greatly upregulated in lesions, whereas a significant decrease in expression of Tie2 and ligands occur under anti-psoriatic treatment (Kuroda et al. J. Invest. Dermatol 2001, 116, 713). Direct association of pathogenesis of disease with Tie2 expression has been demonstrated recently in transgenic mice overexpressing Tie2 (Voskas et al. Am. J. Pathol. 2005, 166, 843). In these mice overexpression of Tie2 causes a psoriasis-like phenotype (such as epidermal thickening, rete ridges and lymphocyte infiltration). These skin abnormalities are resolved completely upon suppression of transgene expression, thereby illustrating a complete dependence on Tie2 signalling for disease maintenance and progression.
Tie2 expression was investigated in human breast cancer specimens and Tie2 expression was found in the vascular endothelium both in normal breast tissue as well as in tumour tissue. The proportion of Tie2-positive microvessels was increased in tumours as compared to normal breast tissue (Peters et al. Br. J. Canc. 1998, 77, 51). However, significant heterogeneity in endothelial Tie2 expression was observed in clinical specimen from a variety of human cancers (Fathers et al. Am. J. Path. 2005, 167, 1753). In contrast, Tie2 and angiopoietins were found to be highly expressed in the cytoplasm of human colorectal adenocarcinoma cells indicating at the potential presence of an autocrine/paracrine growth loop in certain cancers (Nakayama et al. World J. Gastroenterol. 2005, 11, 964). A similar autocrine/paracrine Ang1-Ang2-Tie2 loop was postulated for certain human gastric cancer cell lines (Wang et al. Biochem. Biophys. Res. Comm. 2005, 337, 386).
The relevance of the Ang1-Tie2 signalling axis was challenged with various biochemical techniques. Inhibition of Ang1 expression by an antisense RNA approach resulted in decreased xenograft tumour growth (Shim et al. Int. J. Canc. 2001, 94, 6; Shim et al. Exp. Cell Research 2002, 279, 299). However, other studies report that experimental overexpression of Ang1 in tumour models leads to decreased tumour growth (Hayes et al. Br. J. Canc. 2000, 83, 1154; Hawighorst et al. Am. J. Pathol. 2002, 160, 1381; Stoeltzing et al. Cancer Res. 2003, 63, 3370). The latter results can be rationalized by the ligand's ability to stabilize the endothelial lining of vessels rendering vessels less sensitive for angiogenic stimuli. Interference with the dynamics of Ang1-Tie2 signalling either by over-stimulation or by stimulus deprivation seemingly leads to similar phenotypes.
The pharmacological relevance of inhibiting Tie2 signalling was tested applying various non-small molecule approaches. A peptidic inhibitor of Ang1/2 binding to Tie2 was shown to inhibit Ang1-induced HUVEC migration and angiogenesis induction in an in vivo model (Tournaire et al. EMBO Rep. 2005, 5, 1). Corneal angiogenesis induced by tumour cell conditioned medium was inhibited by a recombinant soluble Tie2 receptor (sTie2) despite the presence of VEGF (Lin et al. J. Clin. Invest. 1997, 100, 2072; see also Singh et al. Biochem. Biophys. Res. Comm. 2005, 332, 194). Gene therapy by adenoviral vector delivered sTie2 was capable of reducing tumour growth rates of a murine mammary carcinoma and a murine melanoma and resulted in reduction of metastasis formation (Lin et al. Proc. Natl. Acad. Sci. USA 1998, 95, 8829). Similar effects were observed with related sTie2 constructs (Siemeister et al. Cancer Res. 1999, 59, 3185) and a Tek-Fc construct (Fathers et al. Am. J. Path. 2005, 167, 1753).
Adenovirus-delivered anti-Tie2 intrabodies were shown to inhibit growth of a human Kaposi's sarcoma and a human colon carcinoma upon peritumoural administration (Popkov et al. Cancer Res. 2005, 65, 972). Histopathological analysis revealed a marked decrease in vessel density in treated vs. control tumours. Phenotypic simultaneous knockout of KDR and Tie2 by an adenovirus delivered intradiabody resulted in significantly higher growth inhibition of a human melanoma xenograft model than KDR knockout alone (Jendreyko et al. Proc. Natl. Acad. Sci. USA 2005, 102, 8293). Similarly, the bispecific Tie2-KDR intradiabody was more active in an in vitro EC tube formation inhibition assay than the two monospecific intrabodies alone (Jendreyko et al. J. Biol. Chem. 2003, 278, 47812). Systematic treatment of tumour-bearing mice with Ang2-blocking antibodies and peptide-Fc fusion proteins led to tumour stasis and elimination of tumour burden in a subset of animals (Oliner et al. Cancer Cell 2004, 6, 507). For a recent report on an immunization approach, see Luo et al. Clin. Cancer Res. 2006, 12, 1813.
However, from the above studies using biochemical techniques to interfere with Tie2 signalling it is not clear, whether similar phenotypes will be observed with small molecule inhibitors of the Tie2 kinase activity. Small molecule inhibitors of kinases by definition block only those cellular effects which are mediated by the receptor's kinase activity and not those which might involve the kinase only as a co-receptor or scaffolding component in multi-enzyme complexes. So far, only a single study using a small molecule Tie2 inhibitor has been published (Scharpfenecker et al. J. Cell Sci. 2005, 118, 771). It remains to be shown that small molecule inhibitors of the Tie2 kinase will be as efficacious in inhibiting angiogenesis as e.g. ligand antibodies, soluble decoy receptors or receptor intrabodies. As discussed above, in certain settings inhibition of Tie2 signalling alone might not be sufficient to induce an adequate antiangiogenic effect. Simultaneous inhibition of several angiogenesis relevant signalling pathways could overcome such inadequacies. In conclusion, there is a great need for novel chemotypes for small mocule inhibitors of the Tie2 kinase. Fine tuning of additive anti-angiogenic activities as well as pharmacokinetic parameters such as e.g. solubility, membrane permeability, tissue distribution and metabolism will finally allow for chosing compounds of accurate profiles for various diseases caused by or associated with dysregulated vascular growth.
PRIOR ART
To date, a small number of therapeutic agents with antiangiogenic activity have been approved for cancer treatment. Avastin (Bevacizumab), a VEGF neutralizing antibody, blocks KDR and VEGFR1 signalling and has been approved for first-line treatment of metastatic colorectal cancer. The small molecule multi-targeted kinase inhibitor Nexavar (Sorafenib) inhibits inter alia members of the VEGFR family and has been approved for the treatment of advanced renal cell carcinoma. Sutent (Sunitinib), another multi-targeted kinase inhibitor with activity vs. VEGFR family members, has been approved by the FDA for treatment of patients with gastrointestinal stromal tumours (GIST) or advanced kidney tumours. Several other small molecule inhibitors of angiogenesis-relevant targets are in clinical and pre-clinical development.
AMG-386, an angiopoietin-targeting recombinant Fc fusion protein, is in phase I clinical development in patients with advanced solid tumours. Several multi-targeted small molecule inhibitors with activity against Tie2 are (or have been) in preclinical evaluation for cancer therapy, including ABT-869, GW697465A and A-422885.88 (BSF466895). The first and most recent compound, however, was reported to possess higher inhibitory activity against other kinase targets including non-angiogenesis kinases and oncogenic kinases. This agent is therefore not considered to be a purely antiangiogenic agent and its applicability to non-cancer diseases remains to be shown.
Pyrazolopyridines have been disclosed as antimicrobiotic substances (e.g. Attaby et al., Phosphorus, Sulphur and Silicon and the related Elements 1999, 149, 49-64; Goda et al. Bioorg. Med. Chem. 2004, 12, 1845). A single 3-amino-1H-pyrazolo[3,4-b]pyridine with modest EGFR inhibitory activity has been published by Cavasotto et al. (Bioorg. Med. Chem. Lett. 2006, 16, 1969). 5-aryl-1H-3-aminopyrazolo[3,4-b]pyridines have been reported as GSK-3 inhibitors (Witherington et al. Bioorg. Med. Chem. Lett. 2003, 13, 1577). WO 2003068773 discloses 3-acylaminopyrazolopyridine derivatives as GSK-3 inhibitors.
DE2232038 and DE2160780 disclose 3-amino-pyrazolo[3,4-b]pyridines i.a. as intermediates for the preparation of azo-dyes.
U.S. Pat. No. 4,224,322, U.S. Pat. No. 4,260,621 and DE2643753 further disclose 3-Amino-pyrazolo[3,4-b]pyridines as antithrombotic substances.
U.S. Pat. No. 5,478,830 further discloses fused heterocycles for the treatment of atherosclerosis.
WO 2001019828 discloses 125 templates, including 3-amino-1H-pyrazolopyridines, as modulators of the activity of receptor and non-receptor tyrosine and serine/threonine kinases.
WO 2002024679 discloses tetrahydropyridine-substituted pyrazolopyridines as IKK inhibitors.
WO 2004076450 further discloses 5-heteroaryl-pyrazolopyridines as p38 inhibitors.
WO 2004113304 discloses indazoles, benzisoxazoles and benzisothiazoles as inhibitors of protein tyrosine kinases, particularly of KDR kinase. However, an exemplary compound from this patent (termed Abt-869; see above) is reported to be ˜40 times less active against Tie2 vs. KDR in enzymatic assays and even ˜1000 times less active against Tie2 than KDR in cellular assays (Albert et al. Mol. Cancer Ther. 2006, 5, 995).
WO 2006/050109 discloses pyrazolopyridines as protein tyrosine kinase inhibitors, particularly as KDR kinase inhibitors.
Technical Problem to be Solved
There is a high demand for compounds which can be used not only as potent inhibitors of Tie-2 kinase, in particular inhibitors not only of the isolated kinase domain, but more importantly of cellular Tie-2 autophosphorylation, for the treatment of diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, but which optionally also display inhibition of a further kinase, the inhibition of which is in response to particular therapeutic needs. Said further kinase may mediate e.g. angiogenesis, inflammation, or may be involved in oncological diseases. More specifically, inhibition of Tie2 or said further kinase can be tuned according to the appropriate therapeutic needs. Such pharmacological profiles are highly desirable for treating diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, in particular solid tumours and metastases thereof, and also for treating non-oncological diseases of dysregulated vascular growth or non-oncological diseases which are accompanied with dysregulated vascular growth, such as retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel, diseases such as coronary and peripheral artery disease.
DESCRIPTION OF THE INVENTION
The solution to the above-mentioned novel technical problem is achieved by providing compounds derived, in accordance with the present invention, from a class of substituted arylpyrazolopyridines and salts thereof, methods of preparing substituted arylpyrazolopyridines, a pharmaceutical composition containing said substituted arylpyrazolopyridines, use of said substituted arylpyrazolopyridines and a method for treating diseases with said substituted arylpyrazolopyridines, all in accordance with the description, as defined in the claims of the present application.
The present invention thus relates to compounds of general formula (I):
Figure US07795264-20100914-C00002
in which:
    • R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
    • R2 stands for hydrogen, —NRd1Rd2, —C(O)Rb, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
    • R4, R5, R6, R7,
    • R8 independently from each other, are selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are optionally substituted one or more times, in the same way or differently, with R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
    • Ra is selected from the group comprising, preferably consisting of, hydrogen or C1-C6-alkyl;
    • Rb is selected from the group comprising, preferably consisting of, hydroxyl, —ORc, —SRc, —NRdRd2, and C1-C6-alkyl;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with —ORc, or —OP(O)(ORc)2;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, or for a —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with halogen, hydroxy or an —ORc, —C(O)Rb, —S(O)2Rb, OP(O)(ORc)2 group, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with an —NRd1Rd2 group; or
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, in the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, in the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
    • A is selected from the group comprising, preferably consisting of, —C(O)—, —C(S)—, —C(═NRa), —C(═NRa)NRa—, —S(O)2—, —S(O)(═NRa), —S(═NRa)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C6-alkylene, or C3-C10-cycloalkylene;
    • D, E are, independently from each other, arylene or heteroarylene; and
    • q represents an integer of 0, 1, or 2;
    • or a salt or an N-oxide, thereof,
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a preferred embodiment, the present invention relates to compounds of general formula (I), in which
    • R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
    • R2 stands for hydrogen, —NRd1Rd2, —C(O)Rb, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
    • R4, R5, R6, R7,
    • R8 independently from each other, are selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are optionally substituted one or more times with R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
    • Ra is selected from the group comprising, preferably consisting of, hydrogen or C1-C6-alkyl;
    • Rb is selected from the group comprising, preferably consisting of, hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with —ORc, or —OP(O)(ORc)2;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, or for a group —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with halogen, hydroxy or an —ORc, —C(O)Rb, —S(O)2Rb, —OP(O)(ORc)2 group, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with the group —NRd1Rd2; or
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
    • A is selected from the group comprising, preferably consisting of, —C(O)—, —S(O)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C6-alkylene, C3-C10-cycloalkylene
    • D is phenylene;
    • E is phenylene or 5- or 6-membered heteroarylene; and
    • q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
    • R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
    • R2 stands for hydrogen, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
    • R4, R5, R6, R7,
    • R8 independently from each other, are selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, —OP(O)(ORc) 2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are optionally substituted one or more times with R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
    • Ra is selected from the group comprising, preferably consisting of, hydrogen or C1-C6-alkyl;
    • Rb is selected from the group comprising, preferably consisting of, hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times with hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with —ORc, or —OP(O)(ORc)2;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, or for a group —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with halogen, hydroxy or an —ORc, —C(O)Rb, —S(O)2Rb, —OP(O)(ORc)2 group, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl are optionally substituted once with an —NRd1Rd2 group; or
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, with a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
    • A is selected from the group comprising, preferably consisting of, —C(O)—, —S(O)2—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C6-alkylene, C3-C10-cycloalkylene;
    • D is para-phenylene;
    • E is phenylene or 5- or 6-membered heteroarylene; and
    • q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a more particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
    • R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
    • R2 stands for hydrogen, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-heterocycloalkyl, aryl, heteroaryl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
    • R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
    • R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R6 is selected from the group comprising, preferably consisting of, hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times with R8;
    • R7 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
    • Ra is hydrogen;
    • Rb is selected from the group comprising, preferably consisting of, —ORc, —NRd1Rd2, and C1-C6-alkyl;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
    • A is selected from the group comprising, preferably consisting of, —C(O)—, —S(O)2—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-C6-cycloalkylene;
    • D is para-phenylene;
    • E is phenylene;
    • q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with an even more particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
    • R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
    • R2 stands for hydrogen, or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or singly or multiply substituted independently from each other with R7;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano;
    • R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
    • R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R6 is selected from the group comprising, preferably consisting of, hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times with R8;
    • R7 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
    • Ra is hydrogen;
    • Rb is selected from the group comprising, preferably consisting of, —ORc, —NRd1Rd2, and C1-C6-alkyl;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
    • A is —C(O)— or —S(O)2—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-cycloalkylene;
    • D is para-phenylene;
    • E is phenylene;
    • q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a yet even more particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which:
    • R1 represents —C(O)Rb or is selected from the group comprising, preferably consisting of, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein said residues are unsubstituted or substituted one or more times, independently from each other, with R6;
    • R2 stands for hydrogen, or C1-C6-alkyl;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, methyl, or fluoro;
    • R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
    • R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R6 is selected from the group comprising, preferably consisting of, hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times with R8;
    • R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
    • Ra is hydrogen;
    • Rb is selected from the group comprising, preferably consisting of, —ORc, and —NRd1Rd2;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
    • A is —C(O)— or —S(O)2—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-cycloalkylene;
    • D is para-phenylene;
    • E is phenylene;
    • q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
In accordance with a yet even more very particularly preferred embodiment, the present invention relates to compounds of general formula (I), in which
    • R1 is C1-C6-alkyl;
    • R2 stands for hydrogen, or C1-C6-alkyl, wherein C1-C6-alkyl is unsubstituted or singly or multiply substituted independently from each other with R7;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, methyl, or fluoro;
    • R4 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —ORc, wherein C1-C6-alkyl is optionally substituted one or more times with R8;
    • R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R7 is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times with R8;
    • R8 is selected from the group comprising, preferably consisting of, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
    • Ra is hydrogen;
    • Rb is selected from the group comprising, preferably consisting of, —ORc, and —NRd1Rd2;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted one or more times with —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are optionally substituted once with —ORc;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or for a —C(O)Rc or —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted one or more times, in the same way or differently, with an —ORc, or —C(O)Rb group, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are optionally substituted once with an —NRd1Rd2 group; or,
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
    • A is —C(O)— or —S(O)2—;
    • B is a bond or a group selected from the group comprising, preferably consisting of C1-C3-alkylene, C3-cycloalkylene;
    • D is para-phenylene;
    • E is phenylene;
    • q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
Even more particularly preferably, the present invention relates to compounds of general formula (I), in which
    • R1 is C1-C3-alkyl;
    • R2 stands for hydrogen or C1-C6-alkyl;
    • R3 is selected from the group comprising, preferably consisting of, hydrogen, methyl, or fluoro;
    • R4 is selected from the group comprising, preferably consisting of, hydrogen, halogen, C1-C3-alkyl, or C1-C3-haloalkyl;
    • R5 is selected from the group comprising, preferably consisting of, hydrogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, —ORc, —NRd1Rd2, wherein C1-C3-alkyl is optionally substituted by R8;
    • R8 is selected from the group comprising, preferably consisting of, —ORc, and —NRd1Rd2;
    • Ra is hydrogen;
    • Rc is selected from the group comprising, preferably consisting of, hydrogen, and C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times with —NRd1Rd2, and wherein C1-C3-alkyl is optionally substituted once with —ORc;
    • Rd1, Rd2 independently from each other are selected from the group comprising, preferably consisting of hydrogen, C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times, in the same way or differently, with an —ORc group, and wherein C1-C3-alkyl is optionally substituted once with an —NRd1Rd2 group; or,
    • Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 6 membered heterocycloalkyl ring, whereby the carbon backbone of this heterocycloalkyl ring is optionally interrupted one time, by a member of the group comprising, preferably consisting of, NH, NRd1, and oxygen;
    • A is —C(O)—;
    • B is C1-C3 alkylene or C3-cycloalkylene;
    • D is para-phenylene;
    • E is phenylene;
    • q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1 or Rd2 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1 or Rd2 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1 or Rd2 within a single molecule to be identical or different. For example, when Ra is present twice in the molecule, then the meaning of the first Ra may be H, for example, and the meaning of the second Ra may be methyl, for example.
DEFINITIONS
The terms as mentioned herein below and in the claims have preferably the following meanings:
The term “alkyl” is to be understood as preferably meaning branched and unbranched alkyl, meaning e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl and decyl and the isomers thereof.
The term “haloalkyl” is to be understood as preferably meaning branched and unbranched alkyl, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen. Particularly preferably, said haloalkyl is, e.g. chloromethyl, fluoropropyl, fluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and isomers thereof.
The term “alkoxy” is to be understood as preferably meaning branched and unbranched alkoxy, meaning e.g. methoxy, ethoxy, propyloxy, iso-propyloxy, butyloxy, iso-butyloxy, tert-butyloxy, sec-butyloxy, pentyloxy, iso-pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy and the isomers thereof.
The term “haloalkoxy” is to be understood as preferably meaning branched and unbranched alkoxy, as defined supra, in which one or more of the hydrogen substituents is replaced in the same way or differently with halogen, e.g. chloromethoxy, fluoromethoxy, pentafluoroethoxy, fluoropropyloxy, difluoromethyloxy, trichloromethoxy, 2,2,2-trifluoroethoxy, bromobutyloxy, trifluoromethoxy, iodoethoxy, and isomers thereof.
The term “cycloalkyl” is to be understood as preferably meaning a C3-C10 cycloalkyl group, more particularly a saturated cycloalkyl group of the indicated ring size, meaning e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl group; and also as meaning an unsaturated cycloalkyl group containing one or more double bonds in the C-backbone, e.g. a C3-C10 cycloalkenyl group, such as, for example, a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl group, wherein the linkage of said cyclolaklyl group to the rest of the molecule can be provided to the double or single bond.
The term “heterocycloalkyl” is to be understood as preferably meaning a C3-C10 cycloalkyl group, as defined supra, featuring the indicated number of ring atoms, wherein one or more ring atom(s) is (are) (a) heteroatom(s) such as NH, NRd1, O, S, or (a) group(s) such as a C(O), S(O), S(O)2, or, otherwise stated, in a Cn-cycloalkyl group, (wherein n is an integer of 3, 4, 5, 6, 7, 8, 9, or 10), one or more carbon atom(s) is (are) replaced by said heteroatom(s) or said group(s) to give such a Cn cycloheteroalkyl group. Thus, said Cn cycloheteroalkyl group refers, for example, to a three-membered heterocycloalkyl, expressed as C3-heterocycloalkyl, such as oxiranyl (C3). Other examples of heterocycloalkyls are oxetanyl (C4), aziridinyl (C3), azetidinyl (C4), tetrahydrofuranyl (C5), pyrrolidinyl (C5), morpholinyl (C6), dithianyl (C6), thiomorpholinyl (C6), piperidinyl (C6), tetrahydropyranyl (C6), piperazinyl (C6), trithianyl (C6) and chinuclidinyl (C8).
The term “halogen” or “Hal” is to be understood as preferably meaning fluorine, chlorine, bromine, or iodine.
The term “alkenyl” is to be understood as preferably meaning branched and unbranched alkenyl, e.g. a vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, or 2-methyl-prop-1-en-1-yl group.
The term “alkynyl” is to be understood as preferably meaning branched and unbranched alkynyl, e.g. an ethynyl, prop-1-yn-1-yl, but-1-yn-1-yl, but-2-yn-1-yl, or but-3-yn-1-yl group.
As used herein, the term “aryl” is defined in each case as having 3-14 carbon atoms, preferably 6-12 carbon atoms, such as, for example, cyclopropenyl, phenyl, tropyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl etc, phenyl being preferred.
As used herein, the term “heteroaryl” is understood as meaning an aromatic ring system which comprises 3-16 ring atoms, preferably 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur, and can be monocyclic, bicyclic, or tricyclic, and in addition in each case can be benzocondensed. Preferably, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.
The term “alkylene”, as used herein in the context of the compounds of general formula (I) is to be understood as meaning an optionally substituted alkyl chain or “tether”, having 1, 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted —CH2— (“methylene” or “single membered tether” or e.g. —C(Me)2-), —CH2—CH2— (“ethylene”, “dimethylene”, or “two-membered tether”), —CH2—CH2—CH2— (“propylene”, “trimethylene”, or “three-membered tether”), —CH2—CH2—CH2—CH2— (“butylene”, “tetramethylene”, or “four-membered tether”), —CH2—CH2—CH2—CH2—CH2— (“pentylene”, “pentamethylene” or “five-membered ether”), or —CH2—CH2—CH2—CH2—CH2—CH2— (“hexylene”, “hexamethylene”, or six-membered tether”) group. Preferably, said alkylene tether is 1, 2, 3, 4, or 5 carbon atoms, more preferably 1 or 2 carbon atoms.
The term “cycloalkylene”, as used herein in the context of the compounds of general formula (I) is to be understood as meaning an optionally substituted cycloalkyl ring, having 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3, 4, 5, or 6, carbon atoms, i.e. an optionally substituted cyclopropyl, cyclobutyl, cyclopenyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl ring, preferably a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
The term “heterocycloalkylene”, as used herein in the context of the compounds of general formula (I) is to be understood as meaning a cycloalkylene ring, as defined supra, but which contains at least one heteroatom which may be identical or different, said heteroatom being such as O, N, S, S(O) or S(O)2.
The term “arylene”, as used herein in the context of the compounds of general formula (I) which include the groups D and E, is to be understood as meaning an optionally substituted monocyclic or polycyclic arylene aromatic system e.g. arylene, naphthylene and biarylene, preferably an optionally substituted phenyl ring or “tether”, having 6 or 10 carbon atoms. More preferably, said arylene tether is a ring having 6 carbon atoms. If the term “arylene” is used it is to be understood that the linking residues can be arranged to each other in ortho-, para- and meta-position, e.g. an optionally substituted moiety of structure
Figure US07795264-20100914-C00003
in which linking positions on the rings are shown as non-attached bonds.
The term “heteroarylene”, as used herein in the context of the compounds of general formula (I) which include the groups D and E, is to be understood as meaning an optionally substituted monocyclic or polycyclic heteroarylene aromatic system, e.g. heteroarylene, benzoheteroarylene, preferably an optionally substituted 5-membered heterocycle, such as, for example, furan, pyrrole, thiazole, oxazole, isoxazole, or thiophene or “tether”, or a 6-membered heterocycle, such as, for example, pyridine, pyrimidine, pyrazine, pyridazine. More preferably, said heteroarylene tether is a ring having 6 carbon atoms, e.g. an optionally substituted structure as shown supra for the arylene moieties, but which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulphur. If the term “heteroarylene” is used it is to be understood that the linking residues can be arranged to each other in ortho-, para- and meta-position.
As used herein, the term “C1-C6”, as used throughout this text, e.g. in the context of the definition of “C1-C6-alkyl”, or “C1-C6-alkoxy”, is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C1-C6” is to be interpreted as any sub-range comprised therein, e.g. C1-C6, C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5 C1-C6; preferably C1-C2, C1-C3, C1-C4, C1-C5, C1-C6; more preferably C1-C4.
Similarly, as used herein, the term “C2-C6”, as used throughout this text, e.g. in the context of the definitions of “C2-C6-alkenyl” and “C2-C6-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C2-C6” is to be interpreted as any sub-range comprised therein, e.g. C2-C6, C3-C5, C3-C4, C2-C3, C2-C4, C2-C5; preferably C2-C3.
As used herein, the term “C3-C10”, as used throughout this text, e.g. in the context of the definitions of “C3-C10-cycloalkyl” or “C3-C10-heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C10” is to be interpreted as any sub-range comprised therein, e.g. C3-C10, C4-C9, C5-C8, C6-C7; preferably C3-C6.
As used herein, the term “C3-C6”, as used throughout this text, e.g. in the context of the definitions of “C3-C6-cycloalkyl” or “C3-C6-heterocycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C4, C4-C6, C5-C6.
As used herein, the term “C6-C11”, as used throughout this text, e.g. in the context of the definitions of “C6-C11-aryl”, is to be understood as meaning an aryl group having a finite number of carbon atoms of 5 to 11, i.e. 5, 6, 7, 8, 9, 10 or 11 carbon atoms, preferably 5, 6, or 10 carbon atoms. It is to be understood further that said term “C6-C11” is to be interpreted as any sub-range comprised therein, e.g. C5-C10, C6-C9, C7-C8; preferably C5-C6.
As used herein, the term “C5-C10”, as used throughout this text, e.g. in the context of the definitions of “C5-C10-heteroaryl”, is to be understood as meaning a heteroaryl group having a finite number of carbon atoms of 5 to 10, in addition to the one or more heteroatoms present in the ring i.e. 5, 6, 7, 8, 9, or 10 carbon atoms, preferably 5, 6, or 10 carbon atoms. It is to be understood further that said term “C5-C10” is to be interpreted as any sub-range comprised therein, e.g. C6-C9, C7-C8, C7-C8; preferably C5-C6.
As used herein, the term “C1-C3”, as used throughout this text, e.g. in the context of the definitions of “C1-C3-alkylene”, is to be understood as meaning an alkylene group as defined supra having a finite number of carbon atoms of 1 to 3, i.e. 1, 2, or 3. It is to be understood further that said term “C1-C3” is to be interpreted as any sub-range comprised therein, e.g. C1-C2, or C2-C3.
As used herein, the term “one or more times”, e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning “one, two, three, four or five times, particularly one, two, three or four tines, more particularly one, two or three times, more particularly one or two times”.
The term “isomers” is to be understood as meaning chemical compounds with the same number and types of atoms as another chemical species. There are two main classes of isomers, constitutional isomers and stereoisomers.
The term “constitutional isomers” is to be understood as meaning chemical compounds with the same number and types of atoms, but they are connected in differing sequences. There are functional isomers, structural isomers, tautomers or valence isomers.
The term “stereoisomers” is to be understood as meaning chemical compounds having atoms which are connected sequentially in the same way, such that condensed formulae for two isomeric molecules are identical. The isomers differ, however, in the way the atoms are arranged in space. There are two major sub-classes of stereoisomers: conformational isomers, which interconvert through rotations around single bonds, and configurational isomers, which are not readily interconvertable.
Configurational isomers are, in turn, can be enantiomers and/or diastereomers. Enantiomers are stereoisomers which are related to each other as mirror images. Enantiomers can contain any number of stereogenic centers, as long as each center is the exact mirror image of the corresponding center in the other molecule. If one or more of these centers differs in configuration, the two molecules are no longer mirror images. Stereoisomers which are not enantiomers are called diastereomers. Diastereomers which still have a different constitution, are another sub-class of diastereomers, the best known of which are simple cis-trans isomers.
In order to limit different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
The compound according to Formula (I) can exist in free form or in a salt form. A suitably pharmaceutically acceptable salt of the pyrazolopyridines of the present invention may be, for example, an acid-addition salt of a pyrazolopyridine of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, para-toluenesulphonic, methylsulphonic, citric, tartaric, succinic or maleic acid. In addition, another suitably pharmaceutically acceptable salt of a pyrazolopyridine of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1-amino-2,3,4-butantriol.
The compound according to Formula (I) can exist as N-oxides which are defined in that at least one nitrogen of the compounds of the general Formula (I) may be oxidized.
The compound according to Formula (I) can exist as solvates, in particular as hydrate, wherein the compound according to Formula (I) may contain polar solvents, in particular water, as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or unstoichiometric ratio. In case of stoichiometric solvates, e.g. hydrate, are possible hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-etc. solvates or hydrates, respectively.
The compounds of the present invention according to Formula (I) can exist as prodrugs, e.g. as in vivo hydrolysable esters. As used herein, the term “in vivo hydrolysable ester” is understood as meaning an in vivo hydrolysable ester of a compound of formula (I) containing a carboxy or hydroxyl group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-C1-C6 alkyl esters, e.g. 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-C6-alkoxycarbonyloxyethyl esters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of formula (I) containing a hydroxyl group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxyl group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxyl include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
The compounds of the present invention according to Formula (I), or salts, N-oxides, or prodrugs thereof, may contain one or more asymmetric centers. Asymmetric carbon atoms may be present in the (R) or (S) configuration or (R,S) configuration. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred stereoisomers are those with the configuration which produces the more desirable biological activity. Separated, pure or partially purified configurational isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification of said isomers and the separation of said isomeric mixtures can be accomplished by standard techniques known in the art.
Further another embodiment of the present invention relates to the use of a compound of general formula (6) as mentioned supra for the preparation of a compound of general formula (I) as defined supra.
The compounds of the present invention can be used in treating diseases of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth. Especially, the compounds effectively interfere with Tie2 signalling. In addition, the compounds of the present invention allow for tunability of the inhibition of an additional kinase target according to the appropriate therapeutic needs.
Therefore, another aspect of the present invention is a use of the compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth.
Preferably, the use is in the treatment of diseases, wherein the diseases are tumours and/or metastases thereof.
Another preferred use is in the treatment of diseases, wherein the diseases are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
A further use is in the treatment of diseases, wherein the diseases are coronary and peripheral artery disease.
Another use is in the treatment of diseases, wherein the diseases are ascites, oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma, chronic lung disease, adult respiratory distress syndrome, bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
Yet another aspect of the invention is a method of treating a disease of dysregulated vascular growth or diseases which are accompanied with dysregulated vascular growth, by administering an effective amount of a compound of general formula (I) described supra.
Preferably, the diseases of said method is tumour and/or metastases thereof.
Also, the diseases of said method are retinopathy, other angiogenesis dependent diseases of the eye, in particular cornea transplant rejection or age-related macular degeneration, e.g. rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis, in particular psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke, and diseases of the bowel.
Further, the disease of the method are coronary and peripheral artery disease.
Other diseases of the method are ascites, oedema such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma, chronic lung disease, adult respiratory distress syndrome, bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation, reduction of scar formation during regeneration of damaged nerves, endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
The compounds of the present invention can thus be applied for the treatment of diseases accompanied by neoangiogenesis. This holds principally for all solid tumours, e.g. breast, colon, renal, lung and/or brain tumours or metastases thereof and can be extended to a broad range of diseases, where pathologic angiogenesis is persistent. This applies for diseases with inflammatory association, diseases associated with oedema of various forms and diseases associated with stromal proliferation and pathologic stromal reactions broadly. Particularly suited is the treatment for gynaecological diseases where inhibition of angiogenic, inflammatory and stromal processes with pathologic character can be inhibited. The treatment is therefore an addition to the existing armament to treat diseases associated with neoangiogenesis.
The compounds of the present invention can be used in particular in therapy and prevention of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment if the tumour growth is accompanied with persistent angiogenesis. However, it is not restricted to tumour therapy but is also of great value for the treatment of other diseases with dysregulated vascular growth. This includes retinopathy and other angiogenesis dependent diseases of the eye (e.g. cornea transplant rejection, age-related macular degeneration), rheumatoid arthritis, and other inflammatory diseases associated with angiogenesis such as psoriasis, delayed type hypersensitivity, contact dermatitis, asthma, multiple sclerosis, restenosis, pulmonary hypertension, stroke and inflammatory diseases of the bowel, such as Crohn's disease. It includes coronary and peripheral artery disease. It can be applied for disease states such as ascites, oedema, such as brain tumour associated oedema, high altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema and macular oedema or oedema following burns and trauma. Furthermore, it is useful for chronic lung disease, adult respiratory distress syndrome. Also for bone resorption and for benign proliferating diseases such as myoma, benign prostate hyperplasia and wound healing for the reduction of scar formation. It is therapeutically valuable for the treatment of diseases, where deposition of fibrin or extracellular matrix is an issue and stroma proliferation is accelerated (e.g. fibrosis, cirrhosis, carpal tunnel syndrome etc). In addition it can be used for the reduction of scar formation during regeneration of damaged nerves, permitting the reconnection of axons. Further uses are endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian hyperstimulation.
Another aspect of the present invention is a pharmaceutical composition which contains a compound of Formula (I) or pharmaceutically acceptable salts thereof, N-oxides, solvates, hydrates, isomers or mixtures of isomers thereof, in admixture with one or more suitable excipients. This composition is particularly suited for the treatment of diseases of dysregulated vascular growth or of diseases which are accompanied with dysregulated vascular growth as explained above.
In order that the compounds of the present invention be used as pharmaceutical products, the compounds or mixtures thereof may be provided in a pharmaceutical composition, which, as well as the compounds of the present invention for enteral, oral or parenteral application contain suitably pharmaceutically acceptable organic or inorganic inert base material, e.g. purified water, gelatin, gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable oils, polyalkylenglycol, etc.
The pharmaceutical compositions of the present invention may be provided in a solid form, e.g. as tablets, dragées, suppositories, capsules or in liquid form, e.g. as a solution, suspension or emulsion. The pharmaceutical composition may additionally contain auxiliary substances, e.g. preservatives, stabilisers, wetting agents or emulsifiers, salts for adjusting the osmotic pressure or buffers.
For parenteral applications, (including intravenous, subcutaneous, intramuscular, intravascular or infusion), sterile injection solutions or suspensions are preferred, especially aqueous solutions of the compounds in polyhydroxyethoxy containing castor oil.
The pharmaceutical compositions of the present invention may further contain surface active agents, e.g. salts of gallenic acid, phosphorlipids of animal or vegetable origin, mixtures thereof and liposomes and parts thereof.
For oral application tablets, dragées or capsules with talcum and/or hydrocarbon-containing carriers and binders, e.g. lactose, maize and potato starch, are preferred. Further application in liquid form is possible, for example as juice, which contains sweetener if necessary.
The dosage will necessarily be varied depending upon the route of administration, age, weight of the patient, the kind and severity of the illness being treated and similar factors. The daily dose is in the range of 0.5 to 1,500 mg. A dose can be administered as unit dose or in part thereof and distributed over the day. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
It is possible for compounds of general formula (I) of the present invention to be used alone or, indeed in combination with one or more further drugs, particularly anti-cancer drugs or compositions thereof. Particularly, it is possible for said combination to be a single pharmaceutical composition entity, e.g. a single pharmaceutical formulation containing one or more compounds according to general formula (I) together with one or more further drugs, particularly anti-cancer drugs, or in a form, e.g. a “kit of parts”, which comprises, for example, a first distinct part which contains one or more compounds according to general formula I, and one or more further distinct parts each containing one or more further drugs, particularly anti-cancer drugs. More particularly, said first distinct part may be used concomitantly with said one or more further distinct parts, or sequentially.
Another aspect of the present invention is a method which may be used for preparing the compounds according to the present invention.
Experimental Details and General Processes
The following table lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. Chemical names were generated using AutoNom2000 as implemented in MDL ISIS Draw. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel in combination with a Flashmaster II autopurifier (Argonaut/Biotage) and eluants such as gradients of hexane/EtOAc or DCM/ethanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluants such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid or aqueous ammonia.
Abbreviation Meaning
Ac Acetyl
Boc tert-butyloxycarbonyl
br Broad
c- cyclo-
Cl chemical ionisation
d Doublet
dd doublet of doublet
DCM Dichloromethane
DIPEA N,N-diisopropylethyl amine
DMAP N,N-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
eq. Equivalent
ESI electrospray ionisation
GP general procedure
HPLC high performance liquid chromatography
LC-MS Liquid chromatography mass spectrometry
m Multiplet
mc centred multiplet
MS mass spectrometry
MTBE methyl-tert-butyl ether
NMR nuclear magnetic resonance spectroscopy:
chemical shifts (δ) are given in ppm.
OTf Trifluoromethylsulphonyl
Pg protecting groups
q Quartet
rf at reflux
r.t. or rt room temperature
s Singlet
Sept. Septet
t Triplet
T3P 1-propanephosphonic acid cyclic anhydride
TEA Triethylamine
TFA trifluoroacetic acid
THF Tetrahydrofuran
The following schemes and general procedures illustrate general synthetic routes to the compounds of general formula I of the invention and are not intended to be limiting. Specific examples are described in the subsequent paragraph.
Figure US07795264-20100914-C00004
Scheme 1 General procedure for the preparation of compounds of the general formula (I), wherein X stands for OTf, Cl, F, OAc, OMe, Y stands for Me, Et and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention.
Compounds of general formula (I) can be synthesized according to the procedure depicted in Scheme 1. Pyridones of general formula 3 are accessible by multi-component coupling of a (hetero)aryl carbaldehyde 1, a methylketone 2, an alkyl cyanoacetate (e.g. methyl cyano acetate or ethyl cyano acetate) and an ammonium salt, preferably ammonium acetate, in a suitable solvent, preferably ethanol, at temperatures up to the boiling point of the solvent, whereby in the case of ethanol 80° C. is preferred.
The so formed pyridones 3 are transformed into pyridines of general formula 4 carrying a leaving group X at the C2 position, wherein X stands for, but is not limited to, trifluoromethanesulfonyl (OTf), acetate (OAc), methoxy (OMe), Cl or F. Preferably, X stands for Cl, even more preferably X stands for OTf. Conversion of intermediate compounds of general formula 3 into intermediates of general formula 4 may be achieved by a variety of methods, e.g. when X═Cl, by reaction with phosphorus oxychloride, optionally in the presence of DMF; or, for example, when X═OTf by reaction with trifluoromethanesulfonic acid anhydride, in the presence of a suitable base, e.g. pyridine, which may also be used as solvent, optionally in the presence of an inert solvent, e.g. dichloromethane, at temperatures ranging from −20° C. to room temperature, whereby 0° C. up to room temperature is preferred.
Reduction of the nitro group in intermediate compounds of general formula 4 gives rise to intermediate compounds of general formula 5. The person skilled in the art is well aware of many methods for nitro group reduction, whereby preferred is the reduction of intermediate compounds of general formula 4 with tin (II) chloride dihydrate in a suitable solvent, e.g. ethanol, at temperatures ranging from room temperature to the boiling point of the solvents, whereby in the case of ethanol 80° C. is preferred.
Intermediate compounds of general formula 6 are formed from intermediate compounds of general formula 5 by reaction with, for example, a suitably functionalized carboxylic acid or acid chloride (leading to carboxylic amides), or a suitably functionalized sulfonyl chloride (leading to sulfonamides), in the presence of a suitable base as necessary, e.g. pyridine, which may also be used as solvent, optionally in the presence of an inert solvent, e.g. dichloromethane, acetonitrile, DMF or THF, at temperatures ranging from −20° C. to the boiling point of the solvent, whereby room temperature is preferred.
Reaction of intermediate compounds of general formula 6 with substituted hydrazines in a suitable solvent, e.g. 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred, leads to compounds of general formula I.
In the case of transformation of amines of general formula 5 into amides, it is also possible to react amines of general formula 5 with an appropriate ester according to a method described in J. Org. Chem. 1995, 8414 in the presence of trimethylaluminium and in suitable solvents such as toluene, at temperatures of 0° C. to the boiling point of the solvent. For amide formation, however, all processes that are known from peptide chemistry to the person skilled in the art are also available. For example, the corresponding acid, which may be obtained from the corresponding ester by saponification, can be reacted with amines of general formula 5 in aprotic polar solvents, such as, for example, DMF, via an activated acid derivative, which is obtainable, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide (DIC), at temperatures of between 0° C. and the boiling point of the solvent, preferably at 80° C., or else with preformed reagents, such as, for example, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (see for example Chem. Comm. 1994, 201), at temperatures of between 0° C. and the boiling point of the solvent, preferably at room temperature, or else with activating agents such as dicyclohexylcarbodiimid (DCC)/dimethylaminopyridine (DMAP) or N-ethyl-N′-dimethylaminopropylcarbodiimide (EDCI)/dimethylaminopyridine (DMAP) or T3P. The addition of a suitable base such as N-methylmorpholine, for example, may be necessary. Amide formation may also be accomplished via the acid halide, mixed acid anhydride, imidazolide or azide.
The carboxylic acids required for the amide coupling reactions above described are either commercially available or are accessible from commercially available carboxylic esters or nitriles. Alternatively, (hetero)aryls bearing a methylenenitrile substituent are easily accessible from the respective halides via a nucleophilic substitution reaction (e.g. KCN, cat. KI, EtOH/H2O). Incorporation of additional functionality into commercially available starting materials can be accomplished by a multitude of aromatic transformation reactions known to the person skilled in the art, including, but not limited to, electrophilic halogenations, electrophilic nitrations, Friedel-Crafts acylations, nucleophilic displacement of fluorine by oxygen nucleophiles and transformation of (hetero)aryl carboxylic acids into amides and subsequent reduction into benzylic amines, whereby the latter two methods are of particular relevance for the introduction of ether and/or aminomethylene side chains.
Benzylic nitrites and esters (and heteroaryl analogs thereof) can be efficiently alkylated at the benzylic position under basic conditions and subsequently hydrolyzed to the corresponding alkylated acids. Conditions for α-alkylations of nitrites and esters include, but are not limited to, the use of alkyl bromides or alkyl iodides as electrophiles under basic conditions in the presence or absence of a phase-transfer catalyst in a mono- or biphasic solvent system. Particularly, by using excess alkyl iodides as electrophilic species α,α-dialkylated nitrites are accessible. More particularly, by using 1,Ω-dihaloalkyls as electrophiles cycloalkyl moieties can be installed at the benzylic position of nitrites and esters (J. Med. Chem. 1975, 18, 144; WO2003022852). The hydrolysis of nitrites to yield carboxylic acids can be accomplished, as known to the person skilled in the art, under acid or base-mediated conditions. As an exemplification of the described general synthetic route toward functionalized carboxylic acids the more particular synthesis of substituted 1-Phenylcyclopropylcarboxylic acids is described in the following scheme (Scheme 2).
Figure US07795264-20100914-C00005
Scheme 2 Preparation of substituted 1-Phenylcyclopropylcarboxylic acids as an exemplification of the general route toward a-alkylated carboxylic acids as substrates for amide formations as described in Scheme 1 and 3, wherein E, R4, and R5 are as defined in the description and claims of this invention
The above described general route to (hetero)aryl-cyclopropyl carboxylic acids is also applicable for the synthesis of the analogous higher homologs of (hetero)aryl-cycloalkyl carboxylic acids.
A variety of substituted hydrazine building blocks required e.g. for the conversion of pyridines 6 into compounds of the general formula (I) is commercially available, either in form of their free base or as various types of salts (e.g. hydrochlorides, oxalates), which can be transformed into their respective free bases by alkaline treatment either before the cyclization or in situ. Additionally, substituted alkyl-, allyl-, and benzylhydrazines (or their respective hydrochloride salts) are accessible from the respective alkyl-, allyl- and benzylhalides, preferably the respective alkyl-, allyl- and benzylbromides, by nucleophilic substitution reaction with a protected hydrazine, e.g. BocNHNH2, in an inert solvent, preferably MeOH, in the presence of an amine promoter, e.g. Et3N, at temperatures ranging from room temperature up to the boiling point of the solvent, followed by deprotection employing conditions known to the person skilled in the art, preferably by treatment with HCl in a mixture of diethyl ether and methanol (for a representative procedure, see J. Med. Chem. 2006, 49, 2170).
The substituents Ra, R1, R2, R3, R4, R5 may be further modified on each step (general formula 1 to general formula 13) or in the last step (general formula I). These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, substitution or other reactions. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999).
Figure US07795264-20100914-C00006
Scheme 3 Alternative general procedure for the preparation of compounds of the general formula (I), wherein X stands for OTf, Cl, F, OAc, OMe, and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention. The 3-amino group at the pyrazolo ring of compounds of the general formula 8, 9, and 10 may be substituted with one or two protecting groups (Pg), preferably one or two Boc groups or even more preferably said amino group may be protected in form of a phthalimide.
An alternative synthetic route toward compounds of general formula (I) is depicted in Scheme 3. Pyridines of the general formula 4, which can be prepared as described above, can be transformed into the respective pyrazolopyridines of general formula 7 by cyclization with substituted hydrazines in a suitable solvent, e.g. 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred.
Protection of the 3-amino group of the pyrazole nucleus leads to compounds of the general formula 8. Suitable protecting groups for amino functions are well known to the person skilled in the art (see for example T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Preferably, the 3-amino group is protected by formation of the respective phthalimide. In particular, phthalimido protection of 3-aminopyrazoles can be achieved by reaction of the amine with phthalic anhydride in a suitable inert solvent, e.g. acetonitrile or dioxane, optionally in the presence of a basic mediator, e.g. Et3N, DIPEA or DMAP, at temperatures from room temperature up to the boiling point of the respective solvent.
Nitro reduction yielding amino compounds of the general formula 9 and e.g. sulfonamide or amide formation to give compounds of general formula 10 are feasible as described above. Finally, the compounds of the present invention (I) are accessible by deprotection of the amino group in compounds of the general formula 10. Preferably, cleavage of the phthalimido group can be achieved, as known to the person skilled in the art, by reaction with hydrazine or hydrazine hydrate in solvents such as EtOH at temperatures from room temperature up to the boiling point of the respective solvent.
Figure US07795264-20100914-C00007
Scheme 4 Additional general procedure for the preparation of compounds of the general formula (I) employing a late-stage N1-functionalization, wherein X stands for OTf, Cl, F, OAc, OMe, and X′ represents OTf, Cl, Br, I, OMs (methanesulfonyl), OAc, and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention.
As a further optional process to compounds of the present invention, introduction of R1-substituents as present in compounds of the present invention of general formula I can be accomplished after formation of 1H-pyrazolopyridines 11 by subsequent acylation or alkylation (Scheme 4). This process is of particular importance if the appropriately substituted hydrazines are not readily available. 1H-Pyrazolopyridines of general formula 11 are accessible from synthetic intermediates of formula 6 (which can be prepared as described above) by cyclization with hydrazine or more preferably with hydrazine hydrate in a suitable solvent, preferably 1-propanol, at temperatures from room temperature up to the boiling point of the solvent, whereby in the case of 1-PrOH 100° C. is preferred. Introduction of R1-groups to yield compounds of the present invention of general formula I can be achieved employing various conditions for introducing substituents to nitrogen atoms as known to the person skilled in the art. These conditions include, but are not limited to, alkylations under basic conditions employing alkyl-, allyl-, benzylhalides or α-halocarbonyl compounds as electrophiles (e.g. WO2005056532; Chem. Pharm. Bull. 1987, 35, 2292; J. Med. Chem. 2005, 48, 6843), alkylations under reductive conditions employing aldehydes as electrophiles and an appropriate reducing agent (e.g. BH3.pyr, NaBH(OAc)3, NaBH3CN, NaBH4), Mitsunobu-type alkylations employing primary or secondary alcohols as electrophiles (e.g. Tetrahedron 2006, 62, 1295; Bioorg. Med. Chem. Lett. 2002, 12, 1687), or N-acylations (see for example J. Med. Chem. 2005, 48, 6843) optionally followed by amide reduction. The presence of the 3-amino group or other nucleophilic nitrogen atoms may give rise to regioisomeric product mixtures under some of these conditions requiring separation of regioisomeric products by methods known to the person skilled in the art. Intermittent protection of the 3-amino group, e.g. by formation of a phthalimido group under conditions as described above, followed by N1 substitution and protective group cleavage may instead allow regioselective introduction of substituents at N1 (see for example US20040235892). Conditions for N1-alkylation of 3-aminopyrazoles of the general formula 11 include, but are not limited to, treatment with an excess of the respective electrophile (e.g. alkyl-, allyl-, benzylhalides or α-halocarbonyl compounds) in the presence of a base, e.g. potassium carbonate or cesium carbonate, in DMF at temperatures from room temperature up to the boiling point of the solvent. Even more preferably, 1H-pyrazoles of general formula 11 are deprotonated with sodium hydride in DMF at temperatures from 0° C. up to 80° C. followed by reaction with the respective electrophile (e.g. alkyl-, allyl-, benzylhalides or α-halocarbonyl compounds) in DMF at temperatures from room temperature up to the boiling point of the solvent.
Figure US07795264-20100914-C00008
Scheme 5 Alternative order of transformations for the preparation of compounds of the general formula (I), wherein X, stands for OTf, Cl, F, OAc, OMe, Y stands for Me, Et and A, B, D, E, Ra, R1, R2, R3, R4, R5 and q are as defined in the description and claims of this invention.
Alternatively to the process shown in Scheme 1, the order of transformations may be changed as exemplified in Scheme 5. A fully functionalized northern part of compounds of the present invention may already be present in aldehydes of general formula 12, which lead upon multicomponent coupling as described above to pyridones of general formula 13. Transformation of pyridones of general formula 13 into pyridines of general formula 6 can be accomplished as described above.
Figure US07795264-20100914-C00009
Scheme 6 Synthesis of pyridones of formula 3a, wherein G stands for C1-C6-alkyl, Y represents Me, Et and D, R3, and q are as defined in the description and claims of this invention.
Scheme 6 depicts the more specific synthesis of pyridones of formula 3a, which in turn may be used as substrates in those conversions described above, especially those in Scheme 1. In addition, methyl ketone 2a may be used in the conversion shown in Scheme 5 replacing substrate 2. Methyl ketone 2a is either commercially available or accessible from the corresponding α-ketoester by alkylation by various conditions known to the person skilled in the art, for example analogous to those described in US20030065212 and U.S. Pat. No. 5,286,723 and those described above. Optionally, the ethyl ester functionality in substrate 2a, in pyridone 3a and subsequent products may be further modified. These modifications may include, but are not limited to, transesterifications, saponifications, amide formations, reductions and subsequent aminations or etherifications or Curtius rearrangements and subsequent amine functionalizations known to the person skilled in the art.
Synthesis of Key Intermediates
In the subsequent paragraphs detailed procedures for the synthesis of key intermediates for compounds of the present invention are described.
In the subsequent paragraphs general procedures for the synthesis of the below mentioned specific example compounds are summarized.
General Procedure 1 (GP1): Pyridone Multi-Component Coupling
To a suspension of ammonium acetate (8 eq.) in EtOH (60 mL per mmol NH4OAc) were added successively the respective methylketone component (1 eq.), methyl cyanoacetate (1 eq.), and 4-nitrobenzaldehyde (1 eq.). The resulting mixture was stirred at reflux for 1-5 h and subsequently for 16 h at r.t. The precipitate was filtered off, washed with EtOH and hexane and dried to yield the pyridone in sufficient purity for use in subsequent transformation without additional purification steps. Concentration of the filtrate gave rise to additional pyridone precipitation improving the overall yield of the multi-component coupling.
General Procedure 2 (GP 2): Triflate Formation
To a solution of the respective pyridone (1 eq.) in DCM (8 mL per mmol pyridone) was added pyridine (1.5 eq.) and subsequently at 0° C. dropwise trifluoromethanesulfonic acid anhydride (1.5 eq.). The resulting mixture was gradually warmed to room temperature and stirring was continued for 2 h. The reaction mixture was diluted with DCM and quenched with water. The aqueous layer was extracted with DCM and the combined organic layers were dried and concentrated in vacuo. Flash column chromatography provided the 2-pyridyl triflates.
General Procedure 3 (GP 3): Nitro Reduction
The respective nitro compound (1 eq.) was dissolved in EtOH (7 mL per mmol nitro compound) and treated in a counterflow of argon portionwise with SnCl2.2H2O (5 eq.). The resulting slurry was vigorously stirred and heated to 70° C., for 30 to 120 min. The reaction mixture was poured into 25% NH3 solution (25 mL per mmol nitro compound), extracted with EtOAc, the combined organic layers were washed with brine twice, dried and concentrated in vacuo. The resulting aniline was usually used for subsequent reactions without additional purification steps.
General Procedure 4 (GP 4): Amide Formation and Cyclization
Step 1
The respective aniline (1 eq.) was dissolved in DCM (12 mL per mmol aniline) and treated with pyridine (1.5 eq.) and the respective carboxylic acid chloride (1.2 eq.; prepared from the respective carboxylic acid by treatment with thionyl chloride and subsequent concentration in vacuo). The reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting aniline (usually 16 h). The reaction mixture was quenched with NaHCO3 and extracted with ethyl acetate. The organic layers were dried and concentrated in vacuo. In most cases, the crude amide was used in the subsequent cyclization without further purification, however, in cases with incomplete amide formation (as judged by TLC) flash column chromatography was applied for purification.
Step 2
The crude or purified amide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol amide) and treated optionally with Et3N (1.5 eq) and subsequently with the respective commercially available substituted hydrazine (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 5 (GP 5): Sulfonamide Formation and Cyclization
Step 1
The respective aniline (1 eq.) was dissolved in DCM (12 mL per mmol aniline) and treated with pyridine (1.5 eq.) and the respective sulfonyl chloride (1.2 eq.). The reaction mixture was stirred at room temperature until TLC indicated complete consumption of the starting aniline (usually 16 h). The reaction mixture was quenched with NaHCO3 and extracted with ethyl acetate. The organic layers were dried and concentrated in vacuo. In most cases, the crude sulfonamide was used in the subsequent cyclization without further purification, however, in cases with incomplete sulfonamide formation (as judged by TLC) flash column chromatography was applied for purification.
Step 2
The crude or purified sulfonamide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol sulfonamide) and treated optionally with Et3N (1.5 eq) and subsequently with the respective commercially available substituted hydrazine (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 6a (GP 6a): Preparation of 1H-pyrazolopyridines (Conditions A)
Step 1
As described for GP 4 step 1.
Step 2
The crude or purified amide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol amide) and treated optionally with Et3N (1.5 eq) and subsequently with 80% hydrazine hydrate (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 6b (GP 6b): Preparation of 1 H-pyrazolopyridines (Conditions B)
Step 1
As described for GP 5 step 1.
Step 2
The crude or purified sulphonamide from step 1 (1 eq.) was dissolved in 1-PrOH (12-15 mL per mmol sulphonamide) and treated optionally with Et3N (1.5 eq) and subsequently with 80% hydrazine hydrate (1-3 eq.). The resulting mixture was stirred at 100° C. for 3 h, concentrated in vacuo and the pyrazolopyridine product was isolated by flash column chromatography followed by re-crystallization and/or preparative HPLC purification.
General Procedure 7 (GP 7): N1-Alkylation of 1H-pyrazolopyridines
The respective 1H-pyrazolopyridine was dissolved in dry DMF under an atmosphere of argon and treated with sodium hydride and subsequently stirred at 50° C. for 1 h.
A solution of the respective alkyl halide in DMF was added dropwise and stirring was continued at 50° C. for 1 h. [In cases were the respective halide is only available as a salt (e.g. hydrochloride or hydrobromide salt), this salt was dissolved in DMF and treated with Et3N, and the resulting slurry was added to the deprotonated 1H-pyrazolopyridine upon filtration through a Millipore filter.] The reaction mixture was diluted with EtOAc, quenched with water, the aqueous layer was extracted with EtOAc and the combined organic layers were dried and concentrated in vacuo. Flash column chromatography optionally followed by recrystallization or preparative HPLC purification yielded the desired alkylated pyrazolopyridines.
General Procedure 8a (GP 8a): Cyclopropanation Conditions A
To a stirred mixture of the respective benzyl cyanide (1.0 eq.), triethylbenzylammonium chloride (2 mol %) and 1,2-dibromoethane (2 eq.) was added dropwise 50% aq. NaOH solution (6-7 eq.). After complete addition the reaction is stirred at 40-50° C. until complete turnover. The reaction mixture was then diluted with water, the organic products extracted with benzene, the combined organic extracts were washed with 15% aq. HCl and subsequently with water, dried and concentrated in vacuo. The crude products were in general used for the subsequent nitrite hydrolysis without further purification.
General Procedure 8b (GP 8b): Cyclopropanation Conditions B
To a stirred mixture of the respective benzyl cyanide (1.0 eq.), triethylbenzylammonium chloride (2 to 4 mol %) and 1-bromo-2-chloroethane (2 to 5 eq.) was added dropwise 50% aq. NaOH solution (6-8 eq.). After complete addition the reaction is stirred at 40-50° C. until complete turnover. The reaction mixture was then diluted with water, the organic products extracted with benzene, the combined organic extracts were washed with 5% aq. HCl and subsequently with water, dried and concentrated in vacuo. The crude products were in general used for the subsequent nitrite hydrolysis without further purification.
General Procedure 9a (GP 9a): Nitrile Hydrolysis Conditions A
To a stirred mixture of the respective substituted phenylcyclopropanecarbonitrile (1.0 eq.) in EtOH (˜7 mL per mmol nitrite) was added a 10% aq. NaOH solution (2.0 to 2.5 eq.) and the resulting mixture was refluxed for 24 h, after which the mixture was concentrated in vacuo and the residual aqueous phase was extracted with MTBE. The aqueous layer was then acidified with concentrated HCl under ice cooling and the thus formed precipitate filtered off. The filter cake was washed with water and dried to yield the analytically pure carboxylic acid.
General Procedure 9b (GP 9b): Nitrile Hydrolysis Conditions B
The respective phenylcyclopropanecarbonitrile (1.0 eq.) together with concentrated HCl (1 mL per mmol nitrite) was stirred in a pressure tube at 100° C. for 16 h. The mixture was poured on ice. After extraction with dichloromethane, the organic extract was washed with water, with brine and dried. After concentration the carboxylic acid crystallized upon standing.
Synthetic Intermediates
Intermediate 1
Preparation of 6-tert-Butyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Figure US07795264-20100914-C00010
In analogy to GP 1, reaction of 61.7 g ammonium acetate (800 mmol, 8 eq.), 10.73 ml ethyl cyanoacetate (100 mmol, 1 eq.), 12.55 ml 3,3-dimethylbutan-2-one (100 mmol, 1 eq.), and 15.12 g 4-nitrobenzaldehyde (100 mmol, 1 eq.) yielded 10.02 g product (34% yield).
1H-NMR (d6-DMSO; 300 MHz): 12.38 (br. s, 1 H); 8.34 (d, 2 H); 7.89 (d, 2 H); 6.28 (s, 1 H); 1.28 (s, 9 H).
MS (ESI): [M+H]+=298.
Intermediate 2
Preparation of 6-Isopropyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Figure US07795264-20100914-C00011
In analogy to GP 1, reaction of 61.7 g ammonium acetate (800 mmol, 8 eq.), 10.67 ml ethyl cyanoacetate (100 mmol, 1 eq.), 10.71 ml 3-methyl-butan-2-one (100 mmol, 1 eq.), and 15.12 g 4-nitrobenzaldehyde (100 mmol, 1 eq.) yielded 4.24 g product (15% yield).
1H-NMR (d6-DMSO; 300 MHz): 12.62 (br. s, 1 H); 8.34 (d, 2 H); 7.87 (d, 2 H); 6.35 (s, 1 H); 2.87 (sept, 1 H); 1.20 (d, 6 H).
MS (ESI): [M+H]+=284.
Intermediate 3
Preparation of 6-Methyl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Figure US07795264-20100914-C00012
In analogy to GP 1, reaction of 8.16 g ammonium acetate (106 mmol, 8 eq.), 1.41 ml ethyl cyanoacetate (13.23 mmol, 1 eq.), 0.98 ml dry acetone (13.23 mmol, 1 eq.), and 2 g 4-nitrobenzaldehyde (13.23 mmol, 1 eq.) yielded 1.56 g product (46% yield).
1H-NMR (d6-DMSO; 400 MHz): 12.76 (br. s, 1 H); 8.34 (d, 2 H); 7.84 (d, 2 H); 6.36 (s, 1 H); 2.30 (s, 3 H).
Intermediate 4
Preparation of 2-[5-Cyano-4-(4-nitro-phenyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-2-methyl-propionic acid ethyl ester
Figure US07795264-20100914-C00013
In analogy to GP 1, reaction of 1.85 g ammonium acetate (24 mmol, 8 eq.), 0.28 ml ethyl cyanoacetate (3 mmol, 1 eq.), 475 mg 2,2-dimethyl-3-oxo-butyric acid ethyl ester (3 mmol, 1 eq.), and 453 mg 4-nitrobenzaldehyde (3 mmol, 1 eq.) yielded 125 mg product (11% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.30 (d, 2 H); 7.79 (d, 2 H); 6.16 (s, 1 H); 4.04 (q, 2 H); 1.41 (s, 6 H); 1.11 (t, 3 H) (isolated as acetate salt).
Intermediate 5
Preparation of 6-Furan-2-yl-4-(4-nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Figure US07795264-20100914-C00014
In analogy to GP 1, reaction of 1.85 g ammonium acetate (24 mmol, 8 eq.), 0.28 ml ethyl cyanoacetate (3 mmol, 1 eq.), 330 mg furan-2-carbaldehyde (3 mmol, 1 eq.), and 453 mg 4-nitrobenzaldehyde (3 mmol, 1 eq.) yielded 362 mg product (39% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.29 (d, 2 H); 7.79 (d, 2 H); 7.73 (m, 1 H); 7.01 (d, 1 H); 6.57 (dd, 1 H); 6.50 (s, 1 H) (isolated as acetate salt).
Intermediate 6
Preparation of 4-(4-Nitro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
Figure US07795264-20100914-C00015
Step 1
In a flask fitted with a Dean-Stark water separator glacial AcOH (6 ml, 0.100 mol) and ammonium acetate (3.85 g, 0.050 mol) were placed. The flask was gently heated to dissolve ammonium acetate. Then a solution of 4-nitroacetophenone (20.6 g, 0.125 mol) in benzene (150 ml) and malononitrile (8.25 g, 0.125 mol) were added. The solution was heated to vigorous reflux during 4 h, cooled, washed with water (3×100 ml), and dried over Na2SO4. Benzene was removed under reduced pressure to give a thick, brown oil. The oil was dissolved in hot ethanol (100 ml), chilled to 0° C., the precipitate was filtered off and dried. Yield 20.9 g (98 mmol, 79%).
1H-NMR (d6-DMSO; 300 MHz): 8.38 (d, 2 H); 7.71 (d, 2 H); 2.40 (s, 3 H).
Step 2
Dimethylformamide dimethyl acetal (10 ml, 72.8 mmol) was added to the suspension of the product from step 1 (13.0 g, 61 mmol) and AcOH (4.4 ml, 72.8 mmol). The mixture was heated until it began to boil. After cooling, 25 ml of isopropanol was added to the mixture, it was filtered, washed with isopropanol and dried. 13.0 g of crude product containing 85% of the desired enamine was obtained.
1H-NMR (CDCl3; 300 MHz): 8.35 (d, 2 H); 7.50 (d, 2 H); 6.50 (d, 1 H); 5.85 (d, 1 H); 3.05 (s, 6 H).
Step 3
The crude enamine from step 2 (13.0 g, 41.2 mmol) was dissolved in acetic acid (130 ml) containing 98% sulfuric acid (26 ml) and water (39 ml). The solution was refluxed for 2 h. After cooling, the precipitate was filtered and washed with water. Yield 6.8 g (28 mmol, 58%).
1H-NMR (DMSO; 300 MHz): 12.80 (br. s, 1 H); 8.40 (d, 2 H); 7.85-7.95 (m, 3 H); 6.5 (d, 1 H);
MS (LCMS): [M+H]+=242.
Intermediate 7
Preparation of Trifluoromethanesulfonic acid 6-tert-butyl-3-cyano-4-(4-nitro-phenyl)-pyridin-2-yl ester
Figure US07795264-20100914-C00016
In analogy to GP 2, reaction of 3.51 g Intermediate 1 (11.8 mmol, 1 eq.), 1.43 mL dry pyridine (17.7 mmol, 1.5 eq.), 2.98 ml trifluoromethanesulfonic acid anhydride (17.7 mmol, 1.5 eq.) in 95 mL DCM yielded 4.42 g 2-pyridyl triflate (10.4 mmol, 88% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.47 (d, 2 H); 8.08 (d, 2 H); 7.93 (s, 1 H); 1.38 (s, 9 H).
Intermediate 8
Preparation of Trifluoromethanesulfonic acid 3-cyano-6-isopropyl-4-(4-nitro-phenyl)-pyridin-2-yl ester
Figure US07795264-20100914-C00017
In analogy to GP 2, reaction of 4.19 g Intermediate 2 (14.8 mmol, 1 eq.), 1.79 mL dry pyridine (22.2 mmol, 1.5 eq.), 3.73 ml trifluoromethanesulfonic acid anhydride (22.2 mmol, 1.5 eq.) in 110 mL DCM yielded 5.6 g 2-pyridyl triflate (13.5 mmol, 91% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.42 (d, 2 H); 8.01 (d, 2 H); 7.87 (s, 1 H); 3.20 (sept, 1 H); 1.24 (d, 6 H).
MS (ESI): [M+H]+=416.
Intermediate 9
Preparation of Trifluoromethanesulfonic acid 3-cyano-6-methyl-4-(4-nitro-phenyl)-pyridin-2-yl ester
Figure US07795264-20100914-C00018
In analogy to GP 2, reaction of 4.5 g Intermediate 3 (17.6 mmol, 1 eq.), 2.13 mL dry pyridine (26.4 mmol, 1.5 eq.), 4.45 ml trifluoromethanesulfonic acid anhydride (26.4 mmol, 1.5 eq.) in 140 mL DCM yielded 2.9 g 2-pyridyl triflate (7.4 mmol, 42% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.42 (d, 2 H); 7.98 (d, 2 H); 7.88 (s, 1 H); 2.62 (S, 3 H).
Intermediate 10
Preparation of Trifluoromethanesulfonic acid 3-cyano-4-(4-nitro-phenyl)-pyridin-2-yl ester
Figure US07795264-20100914-C00019
In analogy to GP 2, reaction of 11.3 g Intermediate 6 (47 mmol, 1 eq.), 5.6 mL dry pyridine (70 mmol, 1.5 eq.), 12 ml trifluoromethanesulfonic acid anhydride (70 mmol, 1.5 eq.) in 450 mL DCM yielded 12.2 g 2-pyridyl triflate (33 mmol, 70% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.85 (d, 1 H); 8.50 (d, 2 H); 8.00-8.20 (m, 3 H).
MS (LCMS): [M+H]+=374.
Intermediate 11
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-6-tert-butyl-3-cyano-pyridin-2-yl ester
Figure US07795264-20100914-C00020
In analogy to GP 3, reaction of 4.7 g Intermediate 7 (11.3 mmol, 1 eq.) with 12.8 g tin(II) chloride dihydrate (56.6 mmol, 5 eq.) in 80 mL EtOH yielded 4 g of the aniline (10 mmol, 88% yield), which was used without further purification.
1H-NMR (d6-DMSO; 400 MHz): 7.61 (s, 1 H); 7.51 (d, 2 H); 6.68 (d, 2 H); 5.91 (br. s, 2 H); 1.29 (s, 9 H).
Intermediate 12
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-3-cyano-6-isopropyl-pyridin-2-yl ester
Figure US07795264-20100914-C00021
In analogy to GP 3, reaction of 5.6 g Intermediate 8 (13.5 mmol, 1 eq.) with 15.6 g tin(II) chloride dihydrate (69.1 mmol, 5 eq.) in 100 mL EtOH yielded the desired amine in a quantitative yield.
1H-NMR (d6-DMSO; 400 MHz): 7.63 (s, 1 H); 7.50 (d, 2 H); 6.67 (d, 2 H); 5.91 (br. s, 2 H); 3.10 (sept, 1 H); 1.20 (d, 6 H).
MS (ESI): [M+H]+=386.
Intermediate 13
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-3-cyano-6-methyl-pyridin-2-yl ester
Figure US07795264-20100914-C00022
In analogy to GP 3, reaction of 866 mg Intermediate 9 (2.24 mmol, 1 eq.) with 2.52 g tin(II) chloride dihydrate (11.18 mmol, 5 eq.) in 11 mL EtOH yielded the desired amine in a quantitative yield.
1H-NMR (d6-DMSO; 300 MHz): 7.66 (s, 1 H); 7.48 (d, 2 H); 6.67 (d, 2 H); 5.91 (br. s, 2 H); 2.52 (s, 3 H).
MS (ESI): [M+H]+=358.
Intermediate 14
Preparation of Trifluoromethanesulfonic acid 4-(4-amino-phenyl)-3-cyano-pyridin-2-yl ester
Figure US07795264-20100914-C00023
In analogy to GP 3, reaction of 5.6 g Intermediate 10 (15 mmol, 1 eq.) with 16.92 g tin(II) chloride dihydrate (75 mmol, 5 eq.) in 75 mL EtOH yielded 4.41 g of the desired product (86% yield).
1H-NMR (d6-DMSO; 300 MHz): 8.52 (d, 1 H); 7.75 (d, 1 H); 7.51 (d, 2 H); 6.68 (d, 2 H); 5.98 (br. s, 2 H).
Non-Commercial Carboxylic Acid Based Building Blocks
Non-commercial carboxylic acid derivatives were prepared as exemplified below:
Figure US07795264-20100914-C00024
GP 8a was applied in the synthesis of the following nitrites
Intermediate E R4 R5
15 phenyl 2-CH3 H
16 phenyl 3-Cl H
17 phenyl 3-F H
GP 8b was applied in the synthesis of the following nitriles:
Intermediate E R4 R5
18 phenyl 3-MeO H
19 phenyl 2-F H
20 phenyl 4-F H
21 phenyl 3-CF3 H
22 phenyl 4-CF3 H
23 phenyl 2-F 5-CF3
GP 9a was applied in the synthesis of the following carboxylic acids:
Intermediate E R4 R5
24 phenyl 2-CH3 H
25 phenyl 3-MeO H
26 phenyl 3-Cl H
27 phenyl 2-F H
28 phenyl 3-F H
29 phenyl 4-F H
GP 9b was applied in the synthesis of the following carboxylic acids:
Intermediate E R4 R5
30 phenyl 3-CF3 H
31 phenyl 4-CF3 H
32 phenyl 2-F 5-CF3
EXAMPLE COMPOUNDS
The following example compounds 1 to 13 were prepared by applying GP 4 or GP 5 using the respective aniline intermediates as resulting from GP 3, the respective carboxylic acid chlorides or sulfonyl chlorides and subsequently methyl hydrazine for cyclization.
1
Figure US07795264-20100914-C00025
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-phenyl- acetamide 1H-NMR: (DMSO, 400 MHz) 10.36 (1H, s); 7.75 (2H, d); 7.51 (2H, d); 7.28-7.33 (4H, m); 7.20-7.24 (1H, m); 6.91 (1H, s); 4.53-4.55 (2H, m); 3.76 (3H, s); 3.65 (2H, s); 1.35 (9H, s).
2
Figure US07795264-20100914-C00026
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-4-methoxy- benzamide 1H-NMR: (DMSO, 300 MHz) 10.26 (1H, s); 7.93-7.97 (4H, m); 7.55 (2H, d); 7.05 (2H, d); 6.96 (1H, s); 4.55-4.57 (2H, m); 3.82 (3H, s); 3.77 (3H, s); 1.37 (9H, s).
3
Figure US07795264-20100914-C00027
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-4-chloro- benzamide 1H-NMR: (DMSO, 300 MHz) 10.49 (1H, s); 7.92-8.00 (4H, m); 7.56-7.62 (4H, m); 6.96 (1H, s); 4.57 (2H, br s); 3.77 (3H, s); 1.37 (9H, s).
4
Figure US07795264-20100914-C00028
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-C-phenyl- methanesulfonamide 1H-NMR: (DMSO, 400 MHz) 10.07 (1H, s); 7.51 (2H, s); 7.25-7.33 (7H, s); 6.93 (1H, s); 4.58-4.60 (2H, m); 4.52 (2H, s); 3.77 (3H, s); 1.36 (9H, s).
5
Figure US07795264-20100914-C00029
 		1-Phenyl- cyclopropanecarboxylic acid [4-(3-amino-6- tert-butyl-1-methyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide 1H-NMR: (DMSO, 400 MHz) 9.31 (1H, s); 7.72 (2H, d); 7.47 (2H, d); 7.24-7.39 (5H, m); 6.90 (1H, s); 4.53 (2H, s); 3.76 (3H, s); 1.42-1.45 (2H, m); 1.35 (9H, s); 1.10-1.13 (2H, m).
6
Figure US07795264-20100914-C00030
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-(3- methoxy-phenyl)- acetamide 1H-NMR: (DMSO, 300 MHz) 10.33 (1H, s); 7.74 (2H, d); 7.51 (2H, d); 7.19-7.24 (1H, m); 6.88-6.92 (3H, m); 6.78- 6.81 (1H, m); 4.55 (2H, br s); 3.76 (3H, s); 3.71 (3H, s); 3.61 (2H,s); 1.35 (9H, s).
7
Figure US07795264-20100914-C00031
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-phenyl- butyramide 1H-NMR: (DMSO, 400 MHz) 10.27 (1H, s); 7.75 (2H, d); 7.49 (2H, d); 7.37-7.39 (2H, m); 7.28-7.32 (2H, m); 7.19- 7.23 (1H, m); 6.90 (1H, s); 4.54 (2H, s); 3.75 (3H, s); 3.56-3.60 (1H, m); 1.99-2.10 (1H, s); 1.63-1.74 (1H, s); 1.34 (9H, s); 0.85 (3H, t).
8
Figure US07795264-20100914-C00032
 		N-[4-(3-Amino-6-tert- butyl-1-methyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-2-phenyl- isobutyramide 1H-NMR: (DMSO, 400 MHz) 9.28 (1H, s); 7.78 (2H, d); 7.48 (2H, d); 7.31-7.36 (4H, m); 7.20-7.24 (1H, m); 6.90 (1H, s); 4.54 (2H, br s); 3.76 (3H, s); 1.55 (6H, s); 1.35 (9H, s).
9
Figure US07795264-20100914-C00033
 		1-(3-Methoxy- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide MS (LC-MS): [M + H]+ = 428.
10
Figure US07795264-20100914-C00034
 		1-(3-Trifluoromethyl- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide 1H-NMR: (DMSO, 300 MHz) 9.57 (s, 1H); 7.72-7.78 (m, 4H); 7.66 (t, 1H); 7.60 (d, 1H); 7.51 (d, 2H); 6.80 (s, 1H); 4.58 (br. 2H); 3.78 (s, 3H); 2.56 (s, 3H);1.53-1.57 (m, 2H); 1.23-1.27 (m, 2H).
11
Figure US07795264-20100914-C00035
 		1-(4-Trifluoromethyl- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide 1H-NMR: (DMSO, 300 MHz) 9.58 (s, 1H); 7.77 (d, 2H); 7.73 (d, 2H); 7.61 (d, 2H); 7.51 (d, 2H); 6.80 (s, 1H); 4.58 (br. s, 2H); 3.78 (s, 3H); 2.56 (s, 3H);1.54-1.58 (m, 2H); 1.22-1.26 (m, 2H).
12
Figure US07795264-20100914-C00036
 		1-(4-Methoxy- phenyl)- cyclopropane- carboxylic acid [4-(3- amino-1,6-dimethyl- 1H-pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide 1H-NMR: (CDCl3, 400 MHz) 7.52 (d, 2H); 7.46 (d, 2H); 7.43 (d, 2H); 6.98 (d, 2H); 6.74 (s, 1H); 4.01 (s, 3H); 3.86 (s, 3H); 2.71 (s, 3H); 1.71-1.73 (m, 2H);1.16- 1.18 (m, 2H).
13
Figure US07795264-20100914-C00037
 		1-Phenyl- cyclopropanecarboxylic acid [4-(3-amino- 1,6-dimethyl-1H- pyrazolo[3,4- b]pyridin-4-yl)- phenyl]-amide 1H-NMR: (DMSO, 400 MHz) 9.28 (s, 1H); 7.71 (d, 2H); 7.45 (d, 2H); 7.32-7.40 (m, 4H); 7.24-7.28 (m, 1H); 6.74 (s, 1H); 4.53 (br. s, 2H); 3.73 (s, 3H); 2.51 (s, 3H); 1.42-1.45 (m,2H); 1.10- 1.13 (m, 2H).
The following exemplary compounds 14 to 65 of the present invention are accessible applying procedures described above using the respective aniline intermediates, as resulting from GP 3, via amide or sulfonamide formation as exemplified above, followed by cyclization with substituted hydrazines. Alternatively, said amide or sulfonamide formation may be followed by cyclization with e.g. 80% hydrazine hydrate, and R1 is introduced in the final step e.g. by alkylation, (compare to GP 4, 5, 6a, 6b and 7):
Figure US07795264-20100914-C00038
Figure US07795264-20100914-C00039
Figure US07795264-20100914-C00040
Figure US07795264-20100914-C00041
Figure US07795264-20100914-C00042
Figure US07795264-20100914-C00043
Figure US07795264-20100914-C00044
Figure US07795264-20100914-C00045
Figure US07795264-20100914-C00046
Figure US07795264-20100914-C00047
Figure US07795264-20100914-C00048
Figure US07795264-20100914-C00049
Figure US07795264-20100914-C00050
Figure US07795264-20100914-C00051
Figure US07795264-20100914-C00052
Figure US07795264-20100914-C00053
Biological Data
Assay 1: Tie2 ELISA Assay
Cellular activity of compounds of the present invention as inhibitors of Tie2 kinase activity was measured employing a Tie2 ELISA assay as described in the following paragraphs. Herein CHO cell-cultures, which are stably transfected by known techniques with Tie2 using DHFR deficiency as selection marker, are stimulated by angiopoietin-2. The specific autophosphorylation of Tie2 receptors is quantified with a sandwich-ELISA using anti-Tie2 antibodies for catch and anti-phosphotyrosine antibodies coupled to HRP for detection.
Materials:
    • 96 well tissue culture plate, sterile, Greiner
    • 96 well FluoroNunc plate MaxiSorp Surface C, Nunc
    • 96 well plate polypropylene for compound dilution in DMSO
    • CHO Tie2/DHFR (transfected cells)
    • PBS−; PBS++, DMSO
    • MEM alpha Medium with Glutamax-I without Ribonucleosides and
      • Deoxyribonucleosides (Gibco #32561-029)
      • with 10% FCS after dialysis! and 1% PenStrep
    • Lysis buffer: 1 Tablet “Complete” protease inhibitor
      • 1 cap Vanadate (1 mL>40 mg/mL; working solution 2 mM)
      • ad 50 mL with Duschl-Puffer
      • pH 7.6
    • Anti-Tie2-antibody 1: 425 in Coating Buffer pH 9.6
      • Stock solution: 1.275 mg/mL>working.: 3 μg/mL
    • PBST: 2 bottles PBS (10×)+10 ml Tween, fill up with VE-water
    • RotiBlock 1:10 in VE-water
    • Anti-Phosphotyrosine HRP-Conjugated 1:10000 in 3% TopBlock
      • 3% TopBlock in PBST
    • BM Chemiluminescence ELISA Substrate (POD)
      • solution B1:100 solution A
    • SF9 cell culture medium
    • Ang2-Fc in SF9 cell culture medium
      Cell Experiment:
    • Dispense 5×104 cells/well/98 μL in 96 well tissue culture plate
    • Incubate at 37° C./5% CO2
    • After 24 h add compounds according to desired concentrations
    • Add also to control and stimulated values without compounds 2 μL DMSO
    • And mix for a few min at room temperature
    • Add 100 μL Ang2-Fc to all wells except control, which receives insect medium
    • Incubate 20 min at 37° C.
    • Wash 3× with PBS++
    • Add 100 μl Lysis buffer/well and shake a couple of min at room temperature
    • Store lysates at 20° C. before utilizing for the ELISA
      Performance of Sandwich-ELISA
    • Coat 96 well FluoroNunc Plate MaxiSorp Surface C with anti-Tie2 mAb
    • 1: 425 in Coating buffer pH 9.6; 100 μL/well overnight at 4° C.
    • Wash 2× with PBST
    • Block plates with 250 μL/well RotiBlock 1:10 in VE-water
    • Incubate for 2 h at room temperature or overnight at 4° C. shaking
    • Wash 2× in PBST
    • Add thawed lysates to wells and incubate overnight shaking at 4° C.
    • Wash 2× with PBST
    • Add 100 μL/well anti-Phosphotyrosine HRP-Conjugated 1:10000 in 3%
    • TopBlock (3% TopBlock in PBST) and incubate overnight under shaking
    • Wash 6× with PBST
    • Add 100 μL/well BM Chemiluminescence ELISA Substrate (POD)
    • solutions 1 und 2 (1:100)
    • Determine luminescence with the LumiCount.
      Assay 2: Tie-2-Kinase HTRF-Assay without Kinase Preactivation
Tie2-inhibitory activity of compounds of the present invention was quantified employing two Tie2 HTRF assay as described in the following paragraphs.
A recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by Glutathion-Sepharose affinity chromatography was used as kinase. Alternatively, commercially available GST-Tie2-fusion protein (Upstate Biotechnology, Dundee, Scotland) can be used As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany). Detection of phosphorylated product is achieved specifically by a trimeric detection complex consisting of the phosphorylated substrate, streptavidin-XLent (SA-XLent) which binds to biotin, and Europium Cryptate-labeled anti-phosphotyrosine antibody PT66 which binds to phosphorylated tyrosine.
Tie-2 (3.5 ng/measurement point) was incubated for 60 min at 22° C. in the presence of 10 μM adenosine-tri-phosphate (ATP) and 1 μM substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH2) with different concentrations of test compounds (0 μM and concentrations in the range 0.001-20 μM) in 5 μl assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl2, 0.5 mM MnCl2, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 5 μl of an aqueous buffer (25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.2 μM, from Cis Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3 ng/μl; a europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer).
The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate peptide. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition) and IC50 values were calculated by a 4 parameter fit using an inhouse software.
Assay 3: Tie-2-Kinase HTRF-Assay with Kinase Preactivation
A recombinant fusion protein of GST and the intracellular domains of Tie-2, expressed in insect cells (Hi-5) and purified by Glutathion-Sepharose affinity chromatography was used as kinase. As substrate for the kinase reaction the biotinylated peptide biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which can be purchased e.g. from the company Biosynthan GmbH (Berlin-Buch, Germany).
For activation, Tie-2 was incubated at a conc. 12.5 ng/μl of for 20 min at 22° C. in the presence of 250 μM adenosine-tri-phosphate (ATP) in assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl2, 0.5 mM MnCl2, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml)].
For the subsequent kinase reaction, the preactivated Tie-2 (0.5 ng/measurement point) was incubated for 20 min at 22° C. in the presence of 10 μM adenosine-tri-phosphate (ATP) and 1 μM substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH2) with different concentrations of test compounds (0 μM and concentrations in the range 0.001-20 μM) in 5 μl assay buffer [50 mM Hepes/NaOH pH 7, 10 mM MgCl2, 0.5 mM MnCl2, 0.1 mM sodium ortho-vanadate, 1.0 mM dithiothreitol, 0.01% NP40, protease inhibitor mixture (“Complete w/o EDTA” from Roche, 1 tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide]. The reaction was stopped by the addition of 5 μl of an aqueous buffer (25 mM Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence) detection reagents streptavidine-XLent (0.2 μM, from Cis Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3 ng/μl; a europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer).
The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate peptide was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate peptide. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition) and IC50 values were calculated by a 4 parameter fit using an inhouse software.
Assay 4: cKIT-Kinase HTRF-Assay
c-Kit-inhibitory activity of compounds of the present invention was quantified employing the c-kit HTRF assay as described in the following paragraphs.
GST-tagged recombinant kinase domain of the human c-kit expressed in SF-9 cells was used as kinase. As substrate for the kinase reaction biotinylated poly-(Glu, Tyr) (Cis biointernational, France) was used.
c-Kit was incubated for 30 min at 22° C. in the presence of different concentrations of test compounds in 5 μl assay buffer [50 mM Hepes/NaOH pH 7.0, 1 mM MgCl2, 5 mM MnCl2, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 10 μM adenosine-tri-phosphate (ATP), 1.3 μg/ml substrate, 0.001% (v/v) Nonidet-P40 (Sigma), 1% (v/v) dimethylsulfoxide]. The concentration of c-kit was adjusted depending of the activity of the enzyme lot and was chosen appropriate to have the assay in the linear range. The reaction was stopped by the addition of 5 μl of a solution of HTRF detection reagents (0.1 μM streptavidine-XLent and 1 nM PT66-Eu-Chelate, an europium-chelate labelled anti-phospho-tyrosine antibody from Perkin Elmer) in an aqueous EDTA-solution (80 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH pH 7.0).
The resulting mixture was incubated 1 h at 22° C. to allow the binding of the biotinylated phosphorylated peptide to the streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the amount of phosphorylated substrate was evaluated by measurement of the resonance energy transfer from the PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm was measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of phosphorylated substrate. The data were normalised (enzyme reaction without inhibitor=0% inhibition, all other assay components but no enzyme=100% inhibition) and IC50 values were calculated by a 4 parameter fit using an inhouse software.
Compounds of the present invention possess enzymatic and cellular activity as inhibitors of Tie2.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.
The entire disclosures of all applications, patents and publications, cited herein and of corresponding European application No. 06090107.1, filed Jun. 13, 2006, and U.S. Provisional Application Ser. No. 60/816,625, filed Jun. 27, 2006, are incorporated by reference herein.
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (23)

1. A compound of formula (I):
Figure US07795264-20100914-C00054
in which:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 stands for hydrogen, —NRd1Rd2, —C(O)Rb, or is selected from branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted, independently from each other, by R7;
R3 is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, and cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7 are each optionally substituted one or more times, in the same way or differently, by R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is hydrogen or C1-C6-alkyl;
Rb is selected from hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are optionally substituted one or more times, in the same way or differently, by hydroxyl, halogen, aryl, or —NRd1Rd2 and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once with —ORc or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, —C(O)Rc, —S(O)2Rb, —C(O)NRd1Rd2, —C(O)Rc, —S(O)2Rb, and —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —ORc, —C(O)Rb, —S(O)2Rb, or —OP(O)(ORc)2 and wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by an —NRd1Rd2 group; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, in the same way or differently, by NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, in the same way or differently, by a —C(O)—, —S(O)—, and/or —S(O)2—, and optionally contains one or more double bonds;
A is selected from —C(O)—, —C(S)—, —C(═NRa)—, —C(═NRa)NRa—, —S(O)2—, —S(O)(═NRa)—, —S(═NRa)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
B is a bond, C1-C6-alkylene, or C3-C10-cycloalkylene;
D, E are, independently from each other, arylene or heteroarylene; and
q represents an integer of 0, 1, or 2;
or a salt or an N-oxide thereof, or an in vivo hydrolysable ester thereof,
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
2. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 stands for hydrogen, —NRd1Rd2, or —C(O)Rb, or is selected from branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4, R5, R6, R7,
R8 independently from each other, are each selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are each optionally substituted one or more times by R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is hydrogen or C1-C6-alkyl;
Rb is selected from hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times by hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by —ORc or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are each hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —ORc, —C(O)Rb, —S(O)2Rb, or —OP(O)(ORc)2, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, by a —C(O)—, —S(O)—, and/or —S(O)2— group, and optionally contains one or more double bonds;
A is selected from —C(O)—, —S(O)2—, —C(S)NRa—, —C(O)C(O)—, —C(O)C(O)NRa—, —C(O)NRaC(O)—, —C(S)NRaC(O)—, and —C(O)NRaC(S)—;
B is a bond, C1-C6-alkylene, or C3-C10-cycloalkylene;
D is phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
3. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 stands for hydrogen, or is selected from branched or unbranched C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-heterocycloalkyl, aryl, and heteroaryl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4, R5, R6, R7,
R8 independently from each other, are selected from hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2, wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R4, R5, R6, and R7, are each optionally substituted one or more times by R8, and wherein C1-C6-alkyl, C3-C10-heterocycloalkyl and C3-C10-cycloalkyl of R8, are optionally substituted once with R8;
Ra is hydrogen or C1-C6-alkyl;
Rb is selected from hydroxyl, —ORc, —SRc, —NRd1Rd2, and C1-C6-alkyl;
Rc is selected from hydrogen, —C(O)Rb, C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl, wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times by hydroxyl, halogen, aryl, or —NRd1Rd2, and wherein C1-C6-alkyl, C1-C6-haloalkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once with —ORc or —OP(O)(ORc)2;
Rd1, Rd2 independently from each other are each hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, aryl, heteroaryl, —C(O)Rc, —S(O)2Rb, or —C(O)NRd1Rd2, wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by halogen, hydroxy, —ORc, —C(O)Rb, —S(O)2Rb, or —OP(O)(ORc)2, and wherein C1-C6-alkyl, C3-C10-cycloalkyl, and C3-C10-heterocycloalkyl are each optionally substituted once by —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 10 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, oxygen or sulphur, and is optionally interrupted one or more times, the same way or differently, by —C(O)—, —S(O)—, and/or —S(O)2—, and optionally contains one or more double bonds;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C6-alkylene, or C3-C10-cycloalkylene;
D is para-phenylene;
E is phenylene or 5- or 6-membered heteroarylene; and
q represents an integer of 0 or 1;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
4. The compound according to claim 1, wherein:
R1 represents —C(O)Rb, or is C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 is H, or is branched or unbranched C1-C6 alkyl, C3-C6-heterocycloalkyl, aryl, or heteroaryl, which in each case is unsubstituted or singly or multiply substituted, independently from each other, by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4 is hydrogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R6 is hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times by R8;
R7 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6haloalkoxy, aryl, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2;
Ra is hydrogen;
Rb is —ORc—NRd1Rd2, and C1-C6-alkyl;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted one or more times, in the same way or differently, by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C(O)Rc or —C(O)NRd1Rd2, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond C1-C3-alkylene, or C3-C6-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being be identical or different.
5. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times, independently from each other, by R6;
R2 is H, or is branched or unbranched C1-C6-alkyl, or C3-C6-heterocycloalkyl, which in each case is unsubstituted or singly or multiply substituted independently from each other by R7;
R3 is hydrogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, halogen, or cyano;
R4 is hydrogen, C1-C6-alkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, nitro, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2; wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are optionally substituted one or more times by R8;
R6 is hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times by R8;
R7 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6 haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2;
Ra is hydrogen;
Rb is selected from —ORc, —NRd1Rd2, and C1-C6-alkyl;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted one or more times by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, —C(O)Rc and —C(O)NRd1Rd2, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
6. The compound according to claim 1, wherein:
R1 represents —C(O)Rb or is selected from C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl, which in each case is unsubstituted or substituted one or more times,
independently from each other, by R6;
R2 stands for hydrogen, or branched or unbranched C1-C6-alkyl;
R3 is hydrogen, methyl, or fluoro;
R4 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R6 is hydrogen, C3-C6-heterocycloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C3-C6-heterocycloalkyl is optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2;
Ra is hydrogen;
Rb is selected from —ORc, and —NRd1Rd2;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, C3-C6-heterocycloalkyl are each optionally substituted one or more times by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, C(O)Rc and —C(O)NRd1Rd2, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd3 or R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
7. The compound according to claim 1, wherein:
R1 is C1-C6-alkyl;
R2 stands for hydrogen, or branched or unbranched C1-C6-alkyl, wherein C1-C6-alkyl is unsubstituted or singly or multiply substituted, independently from each other, by R7;
R3 is hydrogen, methyl, or fluoro;
R4 is hydrogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, or —ORc, wherein C1-C6-alkyl is optionally substituted one or more times by R8;
R5 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R7 is hydrogen, C1-C6-alkyl, C3-C6-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, hydroxy, amino, cyano, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2, wherein C1-C6-alkyl and C3-C6-heterocycloalkyl are each optionally substituted one or more times by R8;
R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2;
Ra is hydrogen;
Rb is —ORc or —NRd1Rd2;
Rc is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, or C3-C6-heterocycloalkyl, wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted one or more times by —NRd1Rd2, and wherein C1-C6-alkyl, C3-C6-cycloalkyl, and C3-C6-heterocycloalkyl are each optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, —C(O)Rc and —C(O)NRd1Rd2 group, wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted one or more times, in the same way or differently, by —ORc, or —C(O)Rb, and wherein C1-C6-alkyl, and C3-C6-cycloalkyl are each optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one or more times, the same way or differently, by NH, NRd1, or oxygen;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1, Rd2 r R8 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1, Rd2 or R8 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1, Rd2 or R8 within a single molecule to be identical or different.
8. The compound according to claim 1 wherein:
R1 is C1-C3-alkyl;
R2 stands for hydrogen or branched or unbranched C1-C6-alkyl;
R3 is hydrogen, methyl, or fluoro;
R4 is hydrogen, halogen, C1-C3-alkyl, or C1-C3-haloalkyl;
R5 is hydrogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-haloalkoxy, halogen, —ORc, or —NRd1Rd2, wherein C1-C3-alkyl is optionally substituted by R8;
R8 is —ORc or —NRd1Rd2;
Ra is hydrogen;
Rc is hydrogen or C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times by —NRd1Rd2, and wherein C1-C3-alkyl is optionally substituted once by —ORc;
Rd1, Rd2 independently from each other are selected from hydrogen and C1-C3-alkyl, wherein C1-C3-alkyl is optionally substituted one or more times, in the same way or differently, by —ORc, and wherein C1-C3-alkyl is optionally substituted once by —NRd1Rd2; or,
Rd1 and Rd2 together with the nitrogen atom to which they are attached, form a 6 membered heterocycloalkyl ring, whereby the carbon backbone of said heterocycloalkyl ring is optionally interrupted one time, by NH, NRd1, or oxygen;
A is —C(O)—;
B is C1-C3 alkylene or C3-cycloalkylene;
D is para-phenylene;
E is phenylene;
q represents an integer of 0;
wherein, when one or more of Ra, Rb, Rc, Rd1 or Rd2 is (are) present in one position in the molecule as well as in one or more further positions in the molecule, said Ra, Rb, Rc, Rd1 or Rd2 has (have), independently from each other, the same meanings as defined above in said first position in the molecule and in said second or further positions in the molecule, it being possible for the two or more occurrences of Ra, Rb, Rc, Rd1 or Rd2 within a single molecule to be identical or different.
9. The compound according to claim 1, wherein said compound is selected from:
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-acetamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-4-methoxy-benzamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-4-chloro-benzamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-C-phenyl-methanesulfonamide;
1-Phenyl-cyclopropanecarboxylic acid [4-(3-amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-(3-methoxy-phenyl)-acetamide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-butyramide;
N-[4-(3-Amino-6-tert-butyl-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-2-phenyl-isobutyramide;
1-(3-Methoxy-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(3-Trifluoromethyl-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(4-Trifluoromethyl-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-(4-Methoxy-phenyl)-cyclopropane-carboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide;
1-Phenyl-cyclopropanecarboxylic acid [4-(3-amino-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-amide; and
pharmaceutically acceptable salts thereof.
10. A method of preparing a compound according to claim 1, said method comprising:
reacting a compound of formula 6
Figure US07795264-20100914-C00055
in which X represents a leaving group,
with a substituted hydrazine of formula 6′:

H2N—NHR1,  6′
to provide a compound of formula (I):
Figure US07795264-20100914-C00056
11. A method of preparing a compound of general formula (I) according to claim 1, said method comprising:
deprotecting an intermediate compound of formula 10
Figure US07795264-20100914-C00057
wherein
Figure US07795264-20100914-C00058
represents a phthalimide-protected amine of formula 10′:
Figure US07795264-20100914-C00059
by reaction with hydrazine,
to provide a compound of formula (I):
Figure US07795264-20100914-C00060
12. A method of preparing a compound according to claim 1, said method comprising:
reacting the step of allowing an intermediate compound of formula 11:
Figure US07795264-20100914-C00061
with a compound of formula 11′:

X′—R1  11′
wherein X′ is a leaving group,
to provide a compound of formula (I):
Figure US07795264-20100914-C00062
13. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier.
14. The compound according to claim 1, wherein R8 is hydrogen, C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-heterocycloalkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, aryl, heteroaryl, hydroxy, amino, halogen, cyano, nitro, —C(O)Rb, —S(O)2Rb, —ORc, —NRd1Rd2, and —OP(O)(ORc)2.
15. The compound according to claim 1, wherein R8 is C1-C6-haloalkoxy, hydroxy, amino, cyano, halogen, —C(O)Rb, —S(O)2Rb, —ORc, or —NRd1Rd2.
16. The compound according to claim 1, wherein
Ra is H;
R2 is H or C1-C6-alkyl;
R3 is H;
A is —C(O)— or —S(O)2—;
B is a bond, C1-C3-alkylene, or C3-cycloalkylene;
D is para-phenylene;
E is phenylene; and
q is 0.
17. The compound according to claim 1, wherein said compound is selected from:
Figure US07795264-20100914-C00063
Figure US07795264-20100914-C00064
Figure US07795264-20100914-C00065
Figure US07795264-20100914-C00066
Figure US07795264-20100914-C00067
Figure US07795264-20100914-C00068
Figure US07795264-20100914-C00069
Figure US07795264-20100914-C00070
Figure US07795264-20100914-C00071
Figure US07795264-20100914-C00072
Figure US07795264-20100914-C00073
Figure US07795264-20100914-C00074
Figure US07795264-20100914-C00075
Figure US07795264-20100914-C00076
18. The compound according to claim 1, wherein R2 is hydrogen.
19. The compound according to claim 1, wherein R2 is methyl.
20. The compound according to claim 1, wherein R2 is tert-butyl.
21. The compound according to claim 1, wherein R2 is branched or unbranched C1-C6-alkyl which is singly or multiply substituted by R7.
22. A process according to claim 10, where in X is trifluoromethylsulphonyl, Cl, F, acetate, or methoxy.
23. A process according to claim 12, where in X′ is trifluoromethylsulphonyl, Cl, Br, I, methanesulfonyl, or acetate.
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